Colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors (KRASi/BRAFi/MEKi/ERKi), has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms including intrinsic and adaptive resistance. Here we report a central role of SRC in mediating intrinsic and adaptive “bypass”-resistance to MEK inhibition in cancer stem cells (CSCs). The SRC oncogene is a well-studied non-receptor tyrosine kinase that can regulate multiple signaling pathways involved in the control of cell proliferation, survival, differentiation, adhesion, invasion and motility. Previously, our laboratory was the first to document that human CRC truncating mutations in the negative regulatory domain of SRC result in SRC activation (Nat Genet 1999). Now our integrated and expansive gene expression signature analyses in >2000 human CRCs reveal that MEKi bypass-resistance is strikingly-correlated with SRC activation, which is associated clinically with regional metastasis, disease recurrence and poor overall survival, and associated biologically with EMT and “stemness”. In support of this, SRC-associated MEKi resistance is strongly related to the CMS4 subtype that has a mesenchymal CSC phenotype. The finding is further supported by in vitro analyses demonstrating that CSCs vs. non-CSCs display greater levels of MEKi-resistance, which is attenuated by a SRC inhibitor. These results support a novel notion that SRC may serve as a common targetable node in MEKi resistance mechanisms, permitting effective cancer stem cell targeting. These pre-clinical data, based on strikingly-correlated pathway analyses of thousands of human tumors, support the “fast-track” development of a biomarker-driven (MEKi + SRCi) drug combination targeting problematic SRC-mediated, mesenchymal CSCs.

Citation Format: Mingli Yang, Thomas B. Davis B. Davis, Michael V. Nebozhyn, Andrey Loboda, Heiman Wang, Michael J. Schell, Lance Pflieger, Ramya Thota, W. Jack Pledger, Timothy J. Yeatman. A novel role of SRC in mediating bypass resistance to MEK inhibition in colorectal cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1083.