Ras inhibitor cancer. Excessive RAS(ON) Signaling Drives 30% of Human Cancers 1.

Ras inhibitor cancer Additionally, immunological approaches utilizing T-cell receptor (TCR)-engineered T cell therapy or vaccines, and Hapimmune antibodies are ongoing. The early-phase drug trials in pancreatic cancer have therefore largely focused on the indirect inhibition of RAS, in particular targeting downstream signaling such as the RAF→MEK→ERK pathway, or on the physical tumor microenvironment, including the desmoplastic reaction that is so characteristic of PDAC. Feb 20, 2024 · KRAS G12C inhibitors have shown clinical responses in KRASG12C -mutant lung cancer, but much less so in colon cancers having the same mutation. Jun 10, 2024 · The development of mutant-selective KRAS inhibitors represents a major therapeutic advance; however, patients can develop resistance through feedback mechanisms and genetic alterations in the RAS pathway. , include EFTX-G12V, an EGFR-directed allele-specific RNAi therapeutic, and MCB-36, a dual-state pan-KRAS degrader Nov 12, 2024 · The team found that delivering SRC and AKT inhibitors along with RAS inhibitors slowed the growth of lung cancer cells more effectively than RAS inhibitors alone, both in lab-grown cells and in mice. We also evaluate the clinical efficacy and safety of mutation-selective and multi-selective inhibitors, in the context of PDAC. Recent advances, reported by Stanland and Huggins et al. Responses with first-generation KRAS G12C inhibitors have been impressive in patients with pretreated advanced non–small cell lung cancer, despite intrinsic treatment resistance mediated by molecular rewiring made possible by smoking-related tumors harboring high tumor mutation burden. Jun 26, 2025 · Figure 1. Here we report the discovery of a Apr 8, 2024 · The inhibitors in this new class of oral medications, being developed by Revolution Medicines Inc. Yet the However, with time, colorectal cancer patients experience resistance to EGFR inhibitors due to ability of RAS to activate the same downstream signaling pathway as EGFR that results through acquired resistance [36, 37]. Keywords: Cancer, Monobody, chemotherapy, allosteric inhibitor, dimerization, RAS GTPase Introduction Nov 30, 2024 · The inhibitor, known as RMC-7977, inhibits the active form (RAS (ON)) of both wild type and mutant RAS proteins. The RAS oncogenes (HRAS, NRAS and KRAS) comprise the most frequently mutated class of oncogenes in human cancers (33%), stimulating intensive effort in developing anti-Ras inhibitors for cancer treatment. Collaboration with Revolution Medicines to Study Biomarkers for RAS (ON) Multi-Selective Inhibitor in Pancreatic Cancer The expanded phase 1 clinical trial is using serial biopsies and blood samples to analyze the tumor response to RMC-6236 at an unprecedented level of detail. Mutations in the RAS oncogenes — most commonly in the KRAS gene — play a role in the three deadliest cancers in the U. Aug 4, 2025 · Combining a multi-selective RAS(ON) inhibitor with CDK4/6 inhibition and CD40 agonism shifts drug-tolerant persister cells towards senescence and promotes durable tumor regression in pancreatic cancer. A recent study highlights the Nov 9, 2024 · However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRAS G12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRAS G12C mutations. RAS has long been viewed as undruggable due to its lack of deep pockets for binding of small molecule inhibitors. Mar 3, 2025 · ADT-007, a first-in-class pan-RAS inhibitor, has unique selectivity for cancer cells with mutant RAS or activated RAS protein and the capability to circumvent resistance to suppress tumor growth, supporting further development of ADT-007 analogs. Dec 2, 2024 · Combined EZH2 and RAS pathway inhibitors kill KRAS- mutant colorectal cancer cells and promote durable tumor regression in vivo. Emerging approaches include the combination of mutant KRAS Mar 13, 2025 · To address the limitations of mutant-specific KRAS inhibitors, we developed and recently characterized ADT-007, a highly potent and selective pan-RAS inhibitor with broad activity against a histologically diverse range of RAS-mutant cancer cell lines. Therapeutic targeting of RAS has been a goal of cancer research for more than 30 years due to its essential role in tumor formation and maintenance. , target the oncogenic or active cancer-causing form of RAS proteins (such as KRAS, NRAS, and HRAS). The inhibitor, known as RMC-7977, inhibits the active form (RAS (ON)) of both wild type and mutant RAS proteins. Paired plasma samples also show early and deep decreases in RAS allele frequency in circulating tumor DNA. May 10, 2024 · In this review, we provide an overview of current standard of care treatment, describe RAS signaling and the relevance of KRAS mutations, and discuss RAS isoform- and mutation-specific differences. There are also newer promising therapies like RMC-6236, a multi-selective RAS inhibitor which is being evaluated in a randomized phase 3 trial for patients with previously treated advanced pancreatic cancer. Dec 15, 2023 · A greater understanding of how oncogenic KRAS drives immune evasion and how mutant-specific KRAS inhibition impacts the tumor microenvironment can lead to novel approaches to combining RAS inhibition with immunotherapies. Jan 7, 2025 · Early clinical trials of RAS inhibitors have shown encouraging results in patients with pancreatic cancer who have a KRAS mutation, However, the cancers are still able to find a way to evade the therapy, leading to relapse. Despite the initial benefit of KRAS-G12C inhibitors for patients with tumors harboring this mutation, the rapid emergence of drug resistance underscores the urgent need to synergize these inhibitors with other Oct 29, 2025 · RAS genes encode molecular switches that control cell growth and survival, and their oncogenic mutations drive many cancers. These compounds offer hope in tackling one of the most formidable challenges in cancer treatment, providing precise and potent tools against RAS-driven tumors. Dec 18, 2023 · RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF -mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. Mar 11, 2024 · Over the past decade, RAS oncogenic proteins have transitioned from being deemed undruggable to having two clinically approved drugs, with several more in advanced stages of development. Abstract RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. , KRAS G12D ), as fi well as groups pan-KRAS inhibitors or (ON) multiselective for inhibitors, are ing clinical trials and ficity, promising results. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants 3. To target the active, GTP-bound state of RAS(ON) directly, we employed an innovative tri-complex inhibitor (TCI) modality. Cocrystal structure (a ternary complex) of daraxonrasib complexed with human KRAS and CypA (PDB ID: 9BG6) is shown (CypA is hidden for clarity). RMC-7977 has demonstrated strong preclinical activity as a multi-selective inhibitor of RAS (ON), especially against cancer models carrying the G12X KRAS codon 12 mutation. Development of best-in-class inhibitors, with optimal potency, selectivity, and pharmacokinetic properties, as well as effective and tolerable combination therapies will be needed to overcome resistance and maximize the clinical impact of RAS-targeted therapy. , p. Oct 30, 2024 · A research team led by MSK physician-scientist Dr. Daraxonrasib binds to the SW (SWI and SWII) regions of KRAS G12V protein and forms several key Nov 1, 2024 · Summary:. Keywords: PDAC, KRAS inhibitor, pancreatic cancer, KRAS, KRAS inhibition Introduction RAS genes (KRAS, HRAS, NRAS) are the most frequently mutated oncogene family, with mutations occurring in 19% of patients with cancer (1). Now, two papers Nov 15, 2024 · Brandon G. Despite decades of efforts, however, it has proven extremely difficult to synthesise clinically effective direct inhibitors of RAS oncoproteins. Direct inhibition of oncogenic RAS has proved difficult, hindering the development of effective therapies for RAS -mutant cancers. Mar 31, 2025 · Activating mutations of Ras are one of the most prevalent drivers of cancer and are often associated with poor clinical outcomes. These new RAS inhibitors have shown promising results in the clinic, leading to early FDA approvals for two RAS inhibitors in lung and colorectal cancer. 3: Overcoming resistance to RAS inhibitors with combination approaches. The in vivo antitumor effects of the ADCs were evaluated on selected cell-derived xenograft (CDX) mice models, where body weight May 7, 2025 · A study of dependencies associated with&nbsp;cancer-causing mutations has identified a small molecule that binds to SHOC2 and inhibits RAS signalling in cells carrying NRAS Q61 mutations, a common May 13, 2024 · There are several potential approaches to this challenge, including targeted inhibitors of more common KRAS mutations, pan-KRAS inhibitors and pan-RAS inhibitors, and immunotherapy-based approaches. Apr 10, 2025 · Background Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. In 1982, the RAS genes HRAS and KRAS were discovered as the first human cancer genes, with KRAS later identified as one of the most frequently mutated oncogenes. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors. Abstract Renin-angiotensin system (RAS) inhibitors (RASi)—widely prescribed for the treatment of cardiovascular diseases—have considerable potential in oncology. Here we provide a personal perspective on the effort leading to our initial report of KRASG12C inhibitors May 28, 2025 · It is a pan-RAS inhibitor, able to target multiple RAS isoforms, including mutations like G12X, G13X, and Q61X as well as targets like G12C, G12D, and wild-type KRAS. However, these inhibitors failed to show any benefits in clinical trials involving KRAS-mutant cancers (3). CRC, colorectal cancer, PDAC pancreatic cancer, NSCLC, non-small cell lung cancer; RAS, rat sarcoma. S. It also sets the stage for additional KRAS inhibitors already in development, researchers said. Its anti‐tumor efficacy is related to the inhibition of multi‐tyrosine kinases involved in tumor progression and angiogenesis [105], though the clinical results for RAS ‐mutated malignancies were disappointing [106], probably due to the insufficient suppression of ERK‐driven cancer growth [107]. (CAMBRIDGE, MASS. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. Jul 4, 2025 · It discusses RAS’ many roles, its associated pathways and relationship to cancer progression, the current status of existing inhibitors, and future strategies for targeting in cancer therapy. Feb 1, 2025 · Numerous combinatorial therapies involving KRAS inhibitors are in clinical trials aiming to overcome therapy resistance. RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Drug discovery and development of daraxonrasib (RMC-6236), a potent, noncovalent RAS (ON) molecular glue inhibitor in multiple clinical trials. The discovery in 2013 by Shokat and collea … May 31, 2023 · Fig. Smaglo, MD, FACP, discusses ongoing research with novel RAS inhibitors in pancreatic cancer. Aug 30, 2024 · KRAS G12C mutant selective inhibitors targeting inactive state have been approved for use in non-small cell lung cancer (NSCLC). Now, a RAS inhibitor thought to Jun 11, 2020 · RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Mar 25, 2025 · A preclinical study from the Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center that combines RAS inhibition and immunotherapy shows promise for future clinical trials in pancreatic cancer treatment strategies. Nov 9, 2024 · However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRAS G12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRAS G12C mutations. 35 In the phase 2 CodeBreaK 100 trial, 126 patients with previously treated KRAS G12C-mutated NSCLC were enrolled and May 22, 2024 · May 22, 2024 | A consortium of pancreatic cancer researchers sharing information in real time has shown that an oral pan-RAS inhibitor known as RMC-7977, developed by Revolution Medicines, effectively targets the common cancer-causing RAS proteins while minimally impacting normal cells—and did so across a comprehensive range of preclinical models in a series of similar experiments. Now, with the success of allele-specific covalent inhibitors against the most frequently mutated version of RAS in Nov 9, 2024 · Other KRAS-mutant inhibitors targeting KRAS G12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Aug 26, 2022 · The RAS oncogenes are among the most common drivers of tumour development and progression but have historically been considered undruggable. 2162See related article by Dilly et al. Mutations can affect proteins that function upstream of RAS, including gain-of-function defects in receptor Mar 19, 2025 · Multidisciplinary collaboration transforms an idea into a potential cancer treatment The RAS Initiative at FNL is the center of the hub-and-spoke model of a worldwide collaboration to investigate the complexity of RAS biology and therapy through the RAS Initiative, established by the National Cancer Institute. Estimatedusing tumor mutation frequencies from Foundation Medicine Insights August 2022 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2023. This has been attributed Jan 24, 2025 · An investigational pan-RAS inhibitor—daraxonrasib (RMC-6236)—shows early activity and has a manageable safety profile in patients with previously treated RAS-mutant PDAC, according to data presented at the 2025 ASCO Gastrointestinal Cancers Symposium (Abstract 722). g. Jul 22, 2025 · A cell-sorting approach reveals distinct modes of cancer resistance to active-state RAS inhibitors. This noncovalent compound targets both the inactive and active form of KRAS G12D, the most common KRAS mutation in PDAC and colorectal cancer. Mar 13, 2025 · ADT-1004 has strong antitumor activity in aggressive and clinically relevant PDAC models with unique selectivity to block RAS-mediated signaling in RAS mutant cells. The platform study design allows combinations of RAS (ON) inhibitors with other anticancer agents to be evaluated in patients with RAS-mutated solid tumors with a focus on GI This is an open-label platform study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS (ON) inhibitors combined with Standard of Care (SOC) or with novel agents Feb 20, 2025 · Although enhancing the GTPase activity of KRAS is an attractive approach to inhibit constitutively active, GTP-bound mutant KRAS, so far this has not been achieved. Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) Nov 1, 2024 · The RAS(ON) multi-selective inhibitor RMC-7977, with or without covalent RAS(ON)G12C targeting, induces sustained regressions in KRAS-mutant NSCLC models, but long-term antitumor activity is curtailed by a mucinous tolerogenic transcriptional state. In this study, we developed a pan-RAS inhibitor, ADT-007, (Z)-2-(5-fluoro-1-(4-h … Jul 3, 2025 · RAS inhibitors have shown early evidence of efficacy in multiple cancer types, but clinical benefit is limited by acquired resistance. 1: Regulation of KRAS and signal transduction pathways. The RAS genes encode small GTP-binding proteins that Mar 14, 2025 · Adding immunotherapy to a new type of inhibitor that targets multiple forms of the cancer-causing gene mutation KRAS kept pancreatic cancer at bay in preclinical models for significantly longer Apr 25, 2025 · The researchers also treated the cancer cells with different drugs and found that the combination of drugs that inhibited both TEAD and RAS led to a more robust tamping down of essential gene expression than either single treatment, thereby supporting the concept of combining TEAD and RAS inhibitors. The research findings—conducted by a consortium of academic researchers led by Columbia scientists and the scientific team Oct 13, 2023 · The therapy uses a different mechanism than approved KRAS G12C inhibitors and targets multiple RAS mutations beyond KRAS G12C BOSTON – RMC-6236, an investigational oral therapeutic that inhibits the active state of multiple RAS variants, was tolerated and exhibited activity in patients with various cancers, according to phase I clinical trial results presented at the AACR-NCI-EORTC Dec 2, 2024 · The development of RAS-directed vaccines may help decrease the likelihood of disease recurrence in patients undergoing treatment for pancreatic cancer. Mar 3, 2025 · Activated RAS is a common driver of cancer that was considered undruggable for decades. May 27, 2025 · Alice Shaw, MD, PhD For several decades, RAS has been considered a potent oncogenic driver; however, until the development of KRAS G12C inhibitors, it was deemed “undruggable. Each year, more than 3 million people are diagnosed with cancers driven by mutations in three RAS-family genes Here, we will discuss the current state of RAS (G12C) inhibitors and the potential for inhibiting additional RAS mutants through targeting RAS dimerization which has emerged as an important step in the allosteric regulation of RAS function. , KRASG12D), as well as pan-KRAS inhibitors or RAS (ON) multiselective inhibitors, are entering clinical trials and demonstrating promising results. The approval, which covers the use of sotorasib for some patients with advanced lung cancer, was based on the results of the CodeBreak100 trial. In this issue, four articles highlight the critical role of nongenetic mechanisms and cell plasticity in mediating resistance to different classes of RAS inhibitors in pancreatic ductal adenocarcinoma and non–small cell lung cancer. Here, using models derived from a patient with NSCLC who progressed May 13, 2022 · Targeted inhibition using small molecule inhibitors works in smoking-related lung cancer. gov NCT06625320). Newer pan-Ras inhibitor strategies include improved direct targeting of R … Jul 23, 2021 · Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. ” “This early success with G12C inhibitors, along with additional key insights into targeting RAS, has fueled this explosion and drug discovery, with numerous new RAS inhibitors now in preclinical and clinical Consistent with preclinical observations, RMC-6236 has shown clinical activity in solid tumors beyond NSCLC and PDAC, and in tumors harboring KRAS or NRAS mutations beyond G12X including RAS-mediated mechanisms of resistance to a targeted BRAF inhibitor May 1, 2024 · Combining KRAS inhibitors with inhibitors of the receptor-tyrosine kinase-RAS-mitogen-activated protein kinase (MAPK) pathway is underway to counteract redundant feedback mechanisms. Jan 8, 2025 · Are there treatments for RAS-mutated lung cancer? Currently there are two RAS inhibitors approved by the U. Aug 4, 2025 · We show that combining a RAS (ON) multi-selective inhibitor with the CDK4/6 inhibitor palbociclib drives persister cells into a senescent-like state, which coincides with improved tumor control and substantial remodeling of the tumor microenvironment. Mar 16, 2025 · Adding immunotherapy to a new type of inhibitor that targets multiple forms of the cancer-causing gene mutation KRAS kept pancreatic cancer at bay in preclinical models for significantly longer Oct 8, 2024 · As an alternative to development of small molecule RAS inhibitors, we have utilized monobody (Mb) technology to study RAS function and identify novel therapeutic vulnerabilities. 2135See related article by Araujo et al. Oct 1, 2018 · RAS is the most commonly mutated oncogene in cancer. 1 KRAS, NRAS, and HRAS are the three main isoforms affected in cancer, of which KRAS is the most mutated, occurring in up to 90% of pancreatic cancer, 50% of colorectal cancer, and 30% of lung adenocarcinoma. RMC-7977 is a highly selective inhibitor Jan 15, 2025 · Recent studies provide new insights into signaling by mutant KRAS, inhibitors of which have provided modest benefits for patients. Sep 9, 2022 · Discover recent advances in RAS inhibitors and emerging therapies targeting the 1 in 5 human cancers involving RAS mutations. Our investigators have years of experience studying RAS and its influence on cancer in the lab and developing and investigating RAS inhibitors in the clinic. Despite FDA approval for two irreversible inhibitors that target the inactive state of KRasG12C, significant unmet clinical need still exists, and the susceptibility of non-G12C mutants to inactive-state inhibition remains unclear. Formation of a complex with an intracellular chaperone protein CypA, an inhibitor, and a target protein RAS blocks effector binding, inhibiting downstream RAS signaling and tumor cell proliferation. Piro Lito discovered that certain inhibitors can short-circuit the out-of-control signaling caused by mutations that fuel cancer growth. Those inhibitors target a specific RAS mutation called KRAS G12C. Jun 14, 2024 · The advent of next-generation RAS inhibitors brings renewed optimism to the care of patients with pancreatic cancer after decades of failure for novel therapeutics. The discovery in 2013 by Shokat and colleagues of a druggable pocket in KRAS paved the way to FDA approval of the first covalently binding Jan 29, 2025 · As such, the emergence of heterocyclic and spirocyclic RAS inhibitors marks a turning point in oncology. Herein Jul 25, 2025 · Consequently, the therapeutic landscape in pancreatic cancer is rapidly evolving due to the increasing number of possible therapeutic options brought by codon-specific KRAS and pan-RAS inhibitors. Evolutionary divergence in the GTPase (G) domain of RAS isoforms is minimal, with only few Dec 27, 2024 · In 1982, the RAS genes HRAS and KRAS were discovered as the first human cancer genes, with KRAS later identified as one of the most frequently mutated oncogenes. Nov 1, 2024 · Here, we evaluated the antitumor activity of the RAS (ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non-small cell lung cancer (NSCLC). : non-small cell lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. Now, with the success of allele-s … Sotorasib, the first KRAS G12C inhibitor approved by the US Food and Drug Administration (FDA) for non–small cell lung cancer (NSCLC), demonstrated clinical efficacy and paved the way for the direct targeting of mutant RAS. The RAS plays a crucial role in cancer biology and affects tumor growth and dissemination directly and indirectly by remodeling the tumor microenvironment. Three publications in Nature and Cancer Discovery describe a promising RAS (on) multi-selective inhibitor that simultaneously targets oncogenic RAS and multiple potential resistance Dec 15, 2023 · Farnesyltransferase inhibitors (FTI) were developed that prevent addition of a farnesyl lipid to the C-terminus of RAS, which is required for association with the plasma membrane. Nov 4, 2024 · Tanios S. Additionally, other mutant-specific inhibitors (e. Food and Drug Administration for the treatment of RAS-mutated non-small cell lung cancer. Revolution Medicines have taken a different approach, developing covalent tri-complex inhibitors that target the active form of RAS, with their multi-RAS and KRAS G12C inhibitor already in clinical trials. Nov 11, 2024 · In experiments in human lung cancer cell lines and mouse models of lung cancer, the researchers found that combining RAS inhibitors with different targeted cancer drugs that reactivate DLC1’s tumor suppressor activity had potent activity against cancer—more potent than that of RAS inhibitors alone. May 5, 2025 · RAS (ON) therapies aim to address resistance by targeting KRAS in its active state, with combination therapies being explored to enhance efficacy. Bekaii-Saab, MD, discusses the evolving role of RAS-targeted therapies in pancreatic cancer and where future research in the field may be headed. The advent of next-generation RAS inhibitors brings renewed optimism to the care of patients with pancreatic cancer after decades of failure for novel therapeutics. Recently, there have been multiple advances in targeting non– KRAS G12C mutations, particularly KRAS G12D. ©2023 The Authors; Published by the American Association for Cancer Research. Aug 12, 2024 · A potent and selective pan-RAS inhibitor, ADT-1004, targeting complex KRAS mutations for pancreatic cancer. Lowy suspects RAS might skew the cellular distribution of proteins in many kinds of cancer. Jan 1, 2025 · In this context, novel inhibitors, such as broad-spectrum inhibitors targeting the active GTP-bound ON-state, pan-RAS ON inhibitors and allele-selective tricomplex inhibitors, have showed promising early clinical activity although their clinical utility needs to be further elucidated. Apr 8, 2024 · Thus, RAS (ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet However, recent advances in chemistry have led to the discovery of multiple new drugs that can inhibit these cancer-causing RAS mutations. KRAS mutations comprise 77% of the RAS mutations in human cancer, making it the most frequently mutated RAS isoform (1). Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. Even 10 years ago, RAS inhibitors were so elusive that RAS was termed ‘undruggable’. However, recent successes in the development of direct RAS inhibitors suggest that the goal of pharmacological inhibition of RAS in Jul 26, 2024 · RAS proteins, central drivers of cancer, appeared ‘undruggable’ for almost 30 years. Yet, it took nearly 40 years to develop clinically effective inhibitors for RAS-mutant cancers. It has been considered a negative feature both due to its impact on prognosis and due to the shallow interface of oncogenic Ras for therapeutic targeting. Sep 6, 2025 · Published in BMC Cancer, the Phase Ia/b trial known as MErCuRIC represents a comprehensive effort to evaluate the dual inhibition of MEK1/2 and MET pathways using binimetinib and crizotinib, respectively, in patients with advanced RAS mutant colorectal cancer. Table 1 provides a summary of current trials of Ras inhibitors. About one-third of all human cancers are driven by mutations of the RAS family of genes. Dec 5, 2024 · In this perspective, Ras peptide inhibitors were revealed to be potential cancer drug candidates, the studies and clinical applications thereof could provide important support for the progress of cancer treatment. Renewed May 27, 2023 · In addition, the development of RAS inhibitors, either direct or indirect, that target the downstream components in RAS pathway is summarized as well. 2183See related May 7, 2025 · Study investigators are aiming to leverage therapy resistance, particularly in patients with solid tumors after receiving available RAS inhibitors. This has been attributed Nov 1, 2024 · Analysis of clinical samples from patients with pancreatic cancer and preclinical models treated with KRAS inhibitors identifies diverse mechanisms of resistance and yields new insights for developing combination therapy strategies. In lung cancer, acquired resistance limits the clinical benefit patients experience. Even 10 years Apr 21, 2025 · Both selective and pan-RAS inhibitors were conjugated to various antibodies via cleavable peptide linkers and ancillary groups to improve druggability. The National Cancer Institute RAS Initiative endeavors to better understand the RAS oncogene and discover its vulnerabilities to treat RAS-related cancers. . Once deemed ‘undruggable’, RAS is now being challenged by innovative inhibitors. Sep 16, 2022 · This co-clinical trial of combined MEK-CDK4/6 inhibition in RAS mutant colorectal cancer demonstrates therapeutic efficacy in patient-derived xenografts and safety in patients, identifies biomarkers of response, and uncovers targetable mechanisms of resistance. May 10, 2024 · Covalent inhibitors of the common mutant isoform of RAS, KRAS(G12C), have begun to unlock the potential of targeting RAS oncoproteins, but limitations to this approach remain. Jan 6, 2025 · Dana-Farber’s Center for RAS Therapeutics is dedicated to discovering new and effective treatments for RAS-driven cancers. These find … Mar 19, 2025 · Research indicates that RAS inhibitors target a specific protein that signals the body to behave in a way that can halt cancer growth. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring The renin-angiotensin system (RAS) regulates physiological functions of the cardiovascular system, kidneys, and other tissues. These RAS “oncoproteins” drive up to a third of all human cancers. Nov 11, 2024 · The first Phase 3 clinical trial of a RAS inhibitor in pancreatic cancer opened to enrollment in October 2024. The primary biological activities of payloads and ADCs were examined in a series of cellular proliferation assays. RMC-6236 is a RAS (ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. See related article by Benitz et al. Jun 30, 2025 · Understand how KRAS G12C inhibitors work, their clinical progress, and challenges with drug resistance in cancer treatment. Jul 5, 2025 · RAS is an oncogene that is commonly mutated in colorectal cancer (CRC). This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET Jul 10, 2025 · RAS mutations are frequently observed in malignant cancers, accounting for around 30% of all cancer cases, and the breakthrough regarding treatment for RAS -mutated cancers is the emergence of pan-RAS inhibitors, which has exhibited significant anti-tumor effects in pre-clinical research and clinical trials. Prior to approval of these therapies, patients with RAS driven non-small cell lung cancers had no targeted therapy options and Jan 24, 2025 · RMC-6236, an investigational pan-RAS inhibitor, shows early activity and has a manageable safety profile in patients with <i>RAS</i>-mutant pancreatic adenocarcinoma (PDAC; Abstract 722). Pan-RAS inhibitors and polo-like kinase 1: promising targets in colorectal cancer Priya Jayachandran 1 , Andrew Elliott 2, Shivani Soni 1, Francesca Battaglin1, Pooja Mittal1, Sandra Algaze1, Jae Nov 30, 2024 · Shubham Pant, MD, MBBS, highlights how pan-RAS inhibitors, RAS-directed vaccines, and biomarker testing can improve outcomes in pancreatic cancer. Fig. Abstract Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations 1,2. Mar 11, 2024 · The RAS proto-oncogene family is very frequently mutated in human tumors, with alterations observed in up to 20% of all cancers. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. The development of direct KRAS inhibitors has changed Apr 16, 2024 · The RAS pathway is one of the most commonly deregulated pathways in human cancer 1. Various in vivo and in vitro studies have shown that RAS plays a pivotal role in the development of malignant tumors, RAS is the most frequently mutated oncogene in cancer and a critical driver of oncogenesis. Jun 25, 2021 · FDA has approved the first KRAS-blocking drug, called sotorasib (Lumakras). Though scientists have known about RAS for more than 30 years, a treatment to block the oncogene has been elusive. Robust Anti-Tumor Activity in Cancer Models Rapid, deep and sustained inhibition drives durable anti-tumor effects across multiple KRASG12C tumor types, with complete responses in some models Nov 30, 2024 · A collaboration of researchers has discovered a promising inhibitor of RAS oncoproteins, which are frequently mutated in human cancers to drive tumor growth. Here, we show that a novel small-molecule inhibitor of a little studied kinase, MAP2K4, while having minor effects in KRAS -mutant cancers when used alone, greatly Jan 24, 2025 · An investigational pan-RAS inhibitor—daraxonrasib (RMC-6236)—shows early activity and has a manageable safety profile in patients with previously treated RAS-mutant PDAC, according to data presented at the 2025 ASCO Gastrointestinal Cancers Symposium (Abstract 722). A recent study highlights the Apr 18, 2024 · Fig. Despite intensive effort, to date no Nov 12, 2024 · In experiments in human lung cancer cell lines and mouse models of lung cancer, the researchers found that combining RAS inhibitors with different targeted cancer drugs that reactivate DLC1’s tumor suppressor activity had potent activity against cancer—more potent than that of RAS inhibitors alone. Jun 3, 2024 · RAS-driven cancers comprise up to 30% of human cancers. and Feng et al. ) December 19, 2024 – Break Through Cancer has launched a collaborative cohort for a Phase 1 study Jul 1, 2025 · This new class of RAS-ON inhibitors could potentially transform the therapeutic landscape for pancreatic cancer, offering more effective targeted treatment options in the near future. Some mutations in the KRAS gene cause this signal to get stuck in the "on" position and cells divide uncontrollably, while additional mutations occur to create cancerous tumors. These agents function by cooperatively suppressing the WNT pathway, driving differentiation, and epigenetically reprogramming cells to permit the induction of apoptotic signals, which then kill these more differentiated tumor cells. Apr 8, 2024 · Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations 1, 2. Jul 3, 2025 · In this article, we review preclinical and clinical data on RAS inhibition in cancer and describe multiple genetic and nongenetic mechanisms of resistance. Additionally, other speci c inhibitors (e. Hopefully, this review will broaden our knowledge on RAS-targeting strategies and trigger more intensive studies on exploiting new RAS allele-specific inhibitors. "K-RAS is a gene that is an on-switch in many of these Mar 8, 2025 · Oncogenic RAS mutations are among the most common in human cancers. Jan 2, 2025 · Nevertheless, KRAS G12C remains the only RAS mutant successfully targeted with FDA-approved inhibitors for cancer treatment in patients, limiting its applicability for other oncogenic RAS mutants, such as G12D, in leukemia. Jun 23, 2025 · The company anticipates that RMC-5127, a RAS (ON) G12V-selective inhibitor, will be its next RAS (ON) inhibitor to enter clinical development. pancreatic With the growing number of RAS tors, patients with mutated KRAS edging closer to an effective cancer therapy. Notably Mar 14, 2025 · Alice Shaw, Chief of Strategic Partnerships at Dana-Farber Cancer Institute, discusses the newly launched Center for RAS Therapeutics. The trial, called RASolute 302, is testing an investigational RAS targeted therapy (RMC-6236) in patients with previously treated, metastatic pancreatic ductal adenocarcinoma (Clinicaltrials. Nov 17, 2025 · What they found The KRAS gene is present in nearly all of our cells and provides the blueprint for a protein called K-Ras that helps signal to cells to divide and grow. Apr 7, 2021 · APPROACHES TO RAS INHIBITION Given the central role of RAS both in carcinogenesis and tumour progression, the RAS oncoprotein is an important therapeutic target. Excessive RAS(ON) Signaling Drives 30% of Human Cancers 1. Even 10 years ago, RAS inhibitors were so elusive that RAS was termed 'undruggable'. 1: Identification of a non-covalent inhibitor that inactivates common cancer-causing KRAS mutants. jluu umrjpv unj nvfe skip wsgo chtqwg xlokuyq ugii gbrxbfr rpkrn qpx czpqd ucvhgyh sdnpz