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RAS Pathway

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.

Mechanism of Action Video Transcript

RAS, which includes KRAS, NRAS, and HRAS, is the most frequently mutated oncogene driving Because cancer has a strong dependence on the RAS pathway, blocking any single target is insufficient because the cancer will maintain its growth and survival through compensatory activation of signaling proteins elsewhere in the RAS pathway or in parallel pathways. For example:

1. ERK constantly suppresses upstream RAF signaling. Phospho-ERK inhibition by MEK-only inhibitors attenuates this suppressive signal to activate RAF kinase and reinvigorate tumor growth. MEK-only inhibition also induces phosphorylation and compensatory parallel pathway activation of FAK and potentially other parallel pathway signaling nodes that can drive tumor growth. Once activated FAK can drive compensatory signaling through pathways, such as PI3K, RhoA and YAP, effectively by-passing RAS pathway blockade and driving tumor growth.

2. Phospho-ERK inhibition by BRAF-only inhibitors also attenuates the suppressive signal from ERK to RAF and induces phosphorylation and compensatory activation of FAK. Avutometinib, which was previously known as VS-6766, is a first in class RAF/MEK clamp that blocks RAF and MEK signaling by holding ARAF, BRAF and CRAF in inactive complexes with MEK, and is the only agent in late-stage clinical development that blocks more than one node in the RAS pathway. In contrast to MEK-only inhibitors, when avutometinib blocks MEK and feedback reactivation of RAF occurs, RAF is now prevented from re-phosphorylating MEK and reactivating the ERK pathway, leading to a more pronounced and sustained response.

Novel combinations may be required to achieve the deepest and most durable response in RAS- mediated cancers. avutometinib has the potential to become a backbone of therapy by combining it with a variety of other agents targeting the RAS pathway and parallel pathways. Preclinical data have shown a strong synergy beween avutometinib in combination with inhibitors of other nodes of the RAS pathway, such as EGFR, KRAS G12C, SHP2, SOS1 and ERK1/2. Synergy of avutometinib with inhibitors of parallel pathway targets, including FAK, CDK4/6, PI3K, AKT and mTOR has also been demonstrated. For example, the combination of avutometinib with the FAK inhibitor, defactinib, blocks both RAF and MEK as well as the compensatory FAK activation for more complete blockade of signaling and tumor growth. Avutometinib has the potential to become the preferred backbone of therapy for a variety of agents targeting the RAS pathway and parallel pathways involved in tumor growth and metastases. With improved control over the RAS signaling network, it is possible to develop customized treatment combinations using avutometinib. Such combinations have the potential to significantly broaden the range of effective treatments available to patients with RAS pathway-driven cancers who currently have limited options.

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)

growth factors and tumor growth

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.

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