Reference Detail

Ref Type Journal Article
PMID (27655129)
Authors McNew KL, Whipple WJ, Mehta AK, Grant TJ, Ray L, Kenny C, Singh A
Title MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling.
Journal Molecular cancer research : MCR
Vol 14
Issue 12
Date 2016 Dec
URL
Abstract Text MEK inhibitors have limited efficacy in treating RAS-RAF-MEK pathway-dependent cancers due to feedback pathway compensation and dose-limiting toxicities. Combining MEK inhibitors with other targeted agents may enhance efficacy. Here, codependencies of MEK, TAK1, and KRAS in colon cancer were investigated. Combined inhibition of MEK and TAK1 potentiates apoptosis in KRAS-dependent cells. Pharmacologic studies and cell-cycle analyses on a large panel of colon cancer cell lines demonstrate that MEK/TAK1 inhibition induces cell death, as assessed by sub-G1 accumulation, in a distinct subset of cell lines. Furthermore, TAK1 inhibition causes G2-M cell-cycle blockade and polyploidy in many of the cell lines. MEK plus TAK1 inhibition causes reduced G2-M/polyploid cell numbers and additive cytotoxic effects in KRAS/TAK1-dependent cell lines as well as a subset of BRAF-mutant cells. Mechanistically, sensitivity to MEK/TAK1 inhibition can be conferred by KRAS and BMP receptor activation, which promote expression of NF-κB-dependent proinflammatory cytokines, driving tumor cell survival and proliferation. MEK/TAK1 inhibition causes reduced mTOR, Wnt, and NF-κB signaling in TAK1/MEK-dependent cell lines concomitant with apoptosis. A Wnt/NF-κB transcriptional signature was derived that stratifies primary tumors into three major subtypes: Wnt-high/NF-κB-low, Wnt-low/NF-κB-high and Wnt-high/NF-κB-high, designated W, N, and WN, respectively. These subtypes have distinct characteristics, including enrichment for BRAF mutations with serrated carcinoma histology in the N subtype. Both N and WN subtypes bear molecular hallmarks of MEK and TAK1 dependency seen in cell lines. Therefore, N and WN subtype signatures could be utilized to identify tumors that are most sensitive to anti-MEK/TAK1 therapeutics.This study describes a potential therapeutic strategy for a subset of colon cancers that are dependent on oncogenic KRAS signaling pathways, which are currently difficult to block with selective agents. Mol Cancer Res; 14(12); 1204-16. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
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
KRAS mutant colon cancer sensitive AZ-TAK1 + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, the combination of AZ-TAK1 and Selumetinib (AZD6244) resulted in an additive effect in colon cancer cells harboring KRAS mutant in culture, demonstrating a 90% growth reduction (PMID: 27655129). 27655129
KRAS mutant colon cancer sensitive AZ-TAK1 Preclinical - Cell culture Actionable In a preclinical study, a colon cancer cell line harboring a KRAS mutation demonstrated sensitivity to AZ-TAK1 in culture, resulting in a 50% cell growth reduction (PMID: 27655129). 27655129
BRAF mutant colon cancer predicted - sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Selumetinib (AZD6244) resulted in some reduced cell growth in colon cancer cells harboring a BRAF mutation in culture (PMID: 27655129). 27655129
KRAS G12V colon cancer sensitive AZ-TAK1 Preclinical - Cell culture Actionable In a preclinical study, a colon cancer cell line harboring KRAS G12V demonstrated sensitivity to AZ-TAK1 in culture, resulting in inhibition of cell growth (PMID: 27655129). 27655129