Biomarkers for Targeted Inhibitors in CMS4 KRAS-Mutated Colorectal Cancers

Over half of colorectal cancers (CRCs) are wired to RAS/RAF/MEK/ERK pathway oncogenic signaling; However, the activity of therapeutic inhibitors targeted at this pathway has been “disappointing,” according to Mingli Yang and colleagues. They investigated MEK inhibition (MEKi)-associated resistance signaling, and CRC subpopulations that may be sensitive to biomarker-informed treatment regimens. In their study, published in BMC Cancer, the team “identified SRC as a common targetable node—an Achilles’ heel—in MEKi-targeted therapy-associated resistance in mesenchymal stem-like CRCs, which may help development of a biomarker-driven drug combination (MEKi + SRCi) to treat problematic subpopulations of CRC.”

Additionally, the study’s authors advised that “Large human tumor gene expression datasets representing CRC heterogeneity can provide deep biological insights heretofore not possible with cell line models, suggesting novel repurposed drug combinations.”

Their investigation included 2250 primary and metastatic human CRC tumors, classified by consensus molecular subtypes (CMS). The researchers then generated multiple gene expression signature scores for each tumor to measure MEK pathway activation, MEKi “bypass” resistance, SRC activation, dasatinib sensitivity, EMT, PC1, Hu-Lgr5-ISC, Hu-EphB2-ISC, Hu-Late TA, Hu-Proliferation, and WNT activity. The expression signatures of interest were validated in two public CRC tumor datasets and one CRC cell line dataset.

The researchers observed a “central role of SRC in mediating ‘bypass’-resistance” to MEK inhibition, primarily in cancer stem cells (CSCs). Their gene signature analysis discovered that MEKi-resistance is “strikingly” correlated with SRC activation, which is likewise associated with epithelial to mesenchymal transition (EMT), regional metastasis, and recurrence with poor prognosis. Moreover, the study’s authors found that “both MEKi-resistance and SRC activation are preferentially associated with a mesenchymal CSC phenotype.” They predicted that MEKi plus SRCi sensitivities are predominantly found in the KRAS mutant, mesenchymal CSC-like CMS4 CRC types.

Ultimately, the authors concluded that there is actual potential to subvert acquired and/or intrinsic resistance in drug-resistant CRCs via targeted inhibition of a common SRC signaling node in patients with selected CRC subtypes.