15417786mcr160173-sup-166415_1_supp_3638114_ccdpwf.png (432.22 kB)
Figure S4 from MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling
figureposted on 2023-04-03, 16:23 authored by Kelsey L. McNew, William J. Whipple, Anita K. Mehta, Trevor J. Grant, Leah Ray, Connor Kenny, Anurag Singh
Regulation of pro-inflammatory cytokine expression and by activated KRAS and BMP receptor signaling.
ARTICLE ABSTRACTMEK 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.Implications: 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.
Cell CycleSignal transduction pathwaysCell Death And SenescenceSurvival factorsCell SignalingAutocrine-paracrine signalingProtein serine-threonine kinasesComputational MethodsGene expression profilingDrug MechanismsCellular responses to anticancer drugsDrug-mediated stimulation of cell death pathwaysGastrointestinal CancersColorectal cancerImmunologyCytokinesSmall Molecule Agents