RAS Pathway: Examining the Most Frequently Mutated Oncogene in Human Cancers
Almost a third of all cancers in patients are associated with mutations of the RAS family of genes, which includes KRAS, NRAS, and HRAS. There are other oncogenes, including EGFR and BRAF, that also activate the RAS pathway—meaning an even higher percentage of cancers depend on this pathway for growth and survival. Patients with a RAS-mutated cancer tend to experience worse outcomes and a higher disease burden than those without RAS pathway mutations. Watch the video to see how customized combinations of avutometinib, a unique RAF/MEK Clamp, including a combination with defactinib, a selective FAK inhibitor, have the potential to greatly expand the number of effective treatments for cancer patients who have limited options today.
Blocking the RAS Pathway Presents Challenges Due to Multiple Resistance Mechanisms
Cancer has a strong affinity for the RAS pathway and reacts to the blocking of any single target by either reactivating the RAS pathway elsewhere or activating parallel pathways to survive. For example, MEK inhibitors paradoxically induce MEK phosphorylation (pMEK) and RAS signaling by relieving ERK-dependent feedback inhibition of RAF. MEK inhibitors also cause compensatory activation of phosphorylated FAK (pFAK), and BRAF inhibition also induces compensatory activation of pFAK. Single-target therapies (eg, MEK inhibitors) are associated with resistance and may not be the best avenue to slowing tumor growth—and finding tolerable combination regimens with MEK inhibitors has been challenging. There has been only modest progress and a limited number of approved therapies. Novel therapies and combinations are urgently needed to deliver on the promise of better outcomes for patients.
Avutometinib (RAF/MEK Clamp)
Avutometinib is a novel RAF/MEK Clamp that confers vertical blockade of the RAS pathway with a single molecule
Avutometinib is a RAF/MEK Clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF, potentially creating a more complete and durable anti-tumor response through maximal RAS pathway inhibition. Avutometinib blocks both RAF and MEK in a single molecule, suggesting it may help overcome resistance and ultimately block against tumor growth and proliferation. By inhibiting RAF phosphorylation of MEK, avutometinib has the advantage of not inducing pMEK, and by inhibiting ERK signaling more completely, preliminary research indicates avutometinib may confer enhanced therapeutic activity. When used alone, preliminary data show that avutometinib demonstrates activity in refractory KRAS-mutant NSCLC adenocarcinoma and across RAS pathway mutations in refractory gynecologic cancers.
Avutometinib offers a novel intermittent dosing schedule and convenient oral regimen with the possibility of better tolerability than currently available MEK-only inhibitors. These characteristics make avutometinib an optimal partner for combination therapy with agents from multiple target classes that may deliver better patient outcomes where they are needed most.
Defactinib (FAK Inhibitor)
As a Parallel Pathway Inhibitor, Defactinib Has Demonstrated Synergy With Avutometinib
Cancer’s strong affinity for the RAS pathway means that it maintains its growth and survival in response to vertical blocking, by either reactivating the RAS pathway elsewhere or activating parallel pathways (eg, PI3K/AKT/mTOR, FAK, RhoA, YAP). Because of this, novel combinations may be required to achieve the deepest and most durable response.
Defactinib (VS-6063) is a selective focal adhesion kinase (FAK) inhibitor that inhibits parallel pathway signaling and has demonstrated synergy with avutometinib. In clinical observations, avutometinib induced elevated pFAK (Y397) as a potential resistance mechanism in the majority of patients, while the combination of avutometinib and defactinib reduced this compensatory pFAK signal.
Exploring the Potential of Defactinib
Defactinib has been assessed as both a monotherapy and in combination with patients with solid tumors. As a monotherapy, defactinib demonstrated clinical activity in heavily pre-treated KRAS-mutant NSCLC and in other advanced non-hematologic malignancies. In both monotherapy and in combination with avutometinib (RAF/MEK Clamp), PD-1 inhibitors, and chemotherapy, defactinib showed a manageable safety profile. Because screens for synergy with defactinib identified MEK inhibitors and avutometinib as potential combination partners, Verastem Oncology is moving forward with clinical development of defactinib in combination with avutometinib and other medications.
Avutometinib as a Backbone of Therapy
The Clinical Development Strategy for Avutometinib Turns Potential into Possible New Treatments
Blocking a single node in the RAS pathway may not provide the best response. For better outcomes, novel combination therapies that address both vertical blockade and parallel inhibition may be needed to achieve the deepest and most durable response. The combination of avutometinib and defactinib provides RAF/MEK vertical blockade and FAK parallel inhibition to overcome key resistance mechanisms.
Combining Avutometinib with Other Agents Gives It the Potential to Become a Backbone of Therapy
Strong preclinical synergy data have been demonstrated with vertical blockers, such as inhibitors of KRAS G12C, EGFR, SHP2, SOS1, and ERK1/2, and parallel pathway inhibitors of FAK, CDK4/6, and PI3K/AKT/mTOR, suggesting a broad range of possible combination partners. Avutometinib also offers favorable tolerability with an established twice-weekly dosing regimen, which may help patients stay on therapy longer.
By better controlling the RAS signaling network, customized RAS-targeted treatment combinations with avutometinib have the potential to greatly expand the number of effective treatment options for specific subsets of cancer patients who have limited options today. This can be life-changing.
