Reference Detail

Ref Type

abstract

PMID

Authors

Eric Haines; Michael Burke; Rachel Catterall; Victor De Jesus; Bin Li; Joseph D. Manna; George Punkosdy; Oksana Zavidij; Sarah R. Wessel; Grace Werosta; Jill Cavanaugh; Sheila Newhouse; Aravind Basavapathruni; Lan Xu; Sergio Santillana; X. Michelle Zhang; Sabine K. Ruppel

Title

Abstract PR10: IK-595, a MEK-RAF complex inhibitor, obviates CRAF mediated resistance resulting in superior RAS/MAPK pathway inhibition and anti-tumor activity in RAS/RAF altered cancers

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular Cancer Research	21	5_Supplement	May 1, 2023

URL

https://aacrjournals.org/mcr/article/21/5_Supplement/PR10/725801/Abstract-PR10-IK-595-a-MEK-RAF-complex-inhibitor

Abstract Text

Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. Although MEK is a clinically validated cancer target and several MEK inhibitors have been approved by the FDA, their clinical utility is limited to BRAFV600 mutant cancers and NF1 mutant neurofibromas. The limitations of these approved MEK inhibitors are inherently related to a narrow therapeutic window and their inability to completely inhibit MAPK signaling. Specifically, RAS mutant cancer cells have a stronger dependency on CRAF for MAPK signal transduction. The MEK inhibition and the subsequent reduction of phosphorylated ERK (pERK) by the approved MEK inhibitors triggers the relief of the ERK-dependent negative feedback control on CRAF, leading to CRAF mediated MEK reactivation and pERK rebound. In addition, CRAF has kinase independent functions that contribute to its anti-tumor apoptotic activities. We developed IK-595, a potent inhibitor of the MEK-RAF complex, to overcome the limitations of available MEK inhibitors. IK-595 stabilizes the MEK-BRAF and MEK-CRAF protein complexes both biochemically and in cells. By trapping MEK in an inactive complex with RAF, it blocks RAF-dependent MEK phosphorylation, limiting CRAF mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS mutant tumors. Importantly, IK-595 demonstrates persistent and further inhibition of ERK phosphorylation than trametinib and VS-6766. This translates to potent inhibition of cell proliferation across a variety of MAPK pathway altered cancer cell lines, including cells with KRAS and NRAS mutations and RAF alterations. Moreover, IK-595 synergizes with KRASG12C, pan-RAF, and mTOR inhibitors in vitro, leading to enhanced anti-proliferation in cancer cells. In addition, IK-595 inhibits MEK and ERK phosphorylation and ERK target gene DUSP6 expression in vivo, driving robust anti-tumor efficacy in multiple KRAS and NRAS mutant, and CRAF amplified, mouse tumor models. Lastly, the pharmacokinetic properties of IK-595 provide a broader therapeutic window compared to available MEK inhibitors. Together, IK-595 is a novel MEK-RAF complex inhibitor that prolongs pathway inhibition, minimizing the potential for resistance, while providing an optimal therapeutic window for patients.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
IK-595	IK-595	1	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
IK-595		IK595\|IK 595		IK-595 inhibits the MEK-RAF complex, which potentially results in reduced tumor cell proliferation and decreased tumor growth (Mol Cancer Res (2023) 21 (5_Supplement): PR10).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS mutant	Advanced Solid Tumor	predicted - sensitive	IK-595	Preclinical	Actionable	In a preclinical study, IK-595 inhibited Mek and Erk phosphorylation and decreased tumor growth in an NRAS-mutant mouse tumor model (Mol Cancer Res (2023) 21 (5_Supplement): PR10).	detail...