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Committed to Ensuring No Cancer Patient Runs Out of Options

RAS pathway-driven cancers are highly aggressive and often recur, so patients rarely experience optimal outcomes. We recognize that too many patients with RAS pathway mutations have been left behind with advances in cancer treatment, and we’re committed to pursuing paths that haven’t been fully explored to deliver better options – and ultimately, more hope for these patients.

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RAS Pathway Mutations Are at the Forefront of Our Research

Almost 30% of all human cancers are driven by mutations in the RAS family of genes that includes KRAS, NRAS and HRAS. Patients with a RAS pathway mutation tend to experience worse outcomes and a more significant impact on their lives than those without RAS pathway mutations.

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Expanding Possibilities for Patients

For many patients with difficult-to-treat cancers, the options have been few. Verastem Oncology aims to change that by relentlessly pursuing RAS-targeted treatment combinations with avutometinib (VS-6766). We’re driven to develop treatments that give patients more choices and the possibility of better outcomes.

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Mechanism of Action Video Transcript

The RAS pathway can be activated by upstream signaling, RAS mutation, or additional mutations in the pathway. RAS, which includes KRAS, NRAS, and HRAS, is the most frequently mutated oncogene driving the growth of approximately 30% of all human cancers. RAS activates RAF, which includes BRAF, CRAF and ARAF. RAF then phosphorylates and activates MEK, which, in turn, phosphorylates and activates ERK to drive tumor growth.

Because cancer has a strong dependence on the RAS pathway, blocking any single target is thought to be insufficient because the cancer will maintain its growth and survival through compensatory activation of signaling proteins elsewhere in the RAS pathway or activation of parallel signaling pathways. For example:

Activated ERK suppresses upstream RAF signaling through a negative feedback loop. Upon binding of a MEK-only inhibitor, phospho-ERK inhibition attenuates this suppressive signal thus activating RAF kinase and stimulating tumor growth. MEK-only inhibition also induces phosphorylation and compensatory activation of Focal Adhesion Kinase and potentially other parallel pathway signaling nodes. Once activated, FAK can drive compensatory signaling through PI3K, RhoA and YAP, effectively by-passing RAS pathway blockade by the MEK-only inhibitor to drive tumor growth.
Phospho-ERK inhibition by BRAF-only inhibitors also attenuates the suppressive signal from ERK to RAF, reactivating RAF. BRAF inhibitors also induce phosphorylation and compensatory activation of FAK.

VS-6766 is a dual RAF/MEK inhibitor that blocks BRAF, CRAF and MEK signaling and is thought to be the only agent in development that blocks more than one node in the RAS pathway. In contrast to MEK-only inhibitors, when VS-6766 blocks MEK and feedback reactivation of RAF occurs, RAF is now prevented from re-phosphorylating MEK and reactivating the ERK pathway, leading to more complete and durable suppression of tumor growth.

Novel combinations may be required to achieve the deepest and most durable response in RAS-driven cancers. VS-6766 has the potential to become a backbone of therapy by combining it with inhibitors of other nodes of the RAS pathway, such as KRAS G12C inhibitors, as well as with inhibitors of key targets in parallel pathways. For example, the combination of VS-6766 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.

By better controlling the RAS signaling network, customized RAS-targeted treatment combinations with VS-6766 have the potential to greatly expand the number of effective treatments for cancer patients who have limited options today.