Revolution Medicines is a clinical-stage biopharmaceutical company developing new treatments for cancer. Its mission is to create targeted medicines for cancers driven by specific genetic mutations. The company’s work focuses on the RAS and mTOR signaling pathways, which are involved in cancer growth. By concentrating on these cellular mechanisms, Revolution Medicines aims to develop therapies for patients with difficult-to-treat cancers.
Targeting RAS Oncogenes
RAS proteins are a family of proteins in cells that regulate cell growth and division. In a healthy cell, these proteins act like a switch, cycling between an “on” state that promotes growth and an “off” state. This controlled cycle ensures that cells divide only when necessary. The instructions for making these proteins come from RAS genes.
Mutations in RAS genes can cause the proteins to become stuck in the “on” position. This malfunction leads to a constant signal for the cell to divide, a hallmark of cancer development. These mutated RAS proteins, known as oncoproteins, drive the growth of approximately 30 percent of all human cancers.
For decades, these cancer-causing RAS proteins were considered “undruggable.” Their smooth structure lacked the distinct pockets that drugs typically bind to, making it difficult to design a molecule to block their activity. This challenge left many patients with RAS-driven cancers without effective targeted therapies, forcing reliance on broader treatments like chemotherapy.
The Tri-Complex Platform
Revolution Medicines developed a scientific approach to address the challenge of drugging RAS oncoproteins. The company’s strategy is centered on a drug discovery platform that creates tri-complex inhibitors. This method targets the active, cancer-causing form of RAS, known as RAS(ON).
The company’s RAS(ON) inhibitors function as molecular matchmakers. These inhibitors first enter a cell and bind to a common intracellular protein called cyclophilin A. Cyclophilin A is a chaperone protein, abundant in human cells, that helps other proteins function correctly.
Once the drug is bound to cyclophilin A, this two-part complex can recognize and attach to the active RAS(ON) oncoprotein. The three components—the inhibitor, cyclophilin A, and the RAS(ON) protein—lock together to form a stable tri-complex. The formation of this structure obstructs the RAS protein, preventing it from sending the continuous growth signals that drive the cancer. This use of a chaperone protein creates a new binding surface, allowing the drug to indirectly inhibit a previously elusive target.
Key Pipeline Candidates
The company is advancing a portfolio of drugs based on its tri-complex platform. One candidate is daraxonrasib (RMC-6236), a RAS(ON) multi-selective inhibitor. This molecule targets a wide range of common RAS mutations, including G12, G13, and Q61, which are prevalent in pancreatic, lung, and colorectal cancers. RMC-6236 is being evaluated in clinical trials for patients with advanced solid tumors harboring these mutations.
Another candidate is elironrasib (RMC-6291), a selective inhibitor targeting the KRAS G12C mutation. While other G12C inhibitors exist, elironrasib utilizes the company’s RAS(ON) targeting approach. This drug is being tested in clinical trials for solid tumors with this mutation, including non-small cell lung cancer (NSCLC).
The pipeline also includes zoldonrasib (RMC-9805), a selective inhibitor for the KRAS G12D mutation, a common driver in cancers like pancreatic cancer. Preclinical studies have shown that combining different inhibitors may produce stronger anti-tumor effects. This could be particularly useful in treating cancers that have developed resistance to other targeted therapies.
Clinical Development and Collaborations
Clinical development programs assess the safety and effectiveness of these new inhibitors. For instance, daraxonrasib (RMC-6236) received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA). This designation is for treating patients with previously treated metastatic pancreatic cancer who have KRAS G12 mutations. The company is also enrolling patients in a global Phase 3 study of daraxonrasib for this cancer, a milestone in its development.
Revolution Medicines has entered into collaborations with major pharmaceutical companies to advance its research. A partnership with Sanofi is centered on developing and commercializing inhibitors that target the mTOR signaling pathway. This is a related area of cancer biology.