Abstract 6192: ERK/AKT pathways may be the wrong effectors for KRAS signaling inhibition in colorectal cancers

Abstract

Abstract Colorectal cancer (CRC) is the third highest incident cancer worldwide and a major cause of cancer death. KRAS protein gain-of-function point mutations play major roles in colorectal tumorigenesis. However, direct inhibition of KRAS is challenging as its protein structure is inadmissible to inhibitor docking. Efforts have been diverted to inhibit downstream RAF/MEK/ERK and PI3K/Akt signaling. Nevertheless, none of these inhibitors has progressed to clinical use in CRC despite extensive trials over the past few decades. We examined levels of phospho-ERK1/2(T202/Y204) and phospho-Akt1/2/3(S473) in human colorectal tumor and matched mucosa at least 10 cm away with quantitative near infrared western blot and immunofluorescence imaging. Surprisingly, 75.5% (25/33) of tumors has lower or equivalent phospho-ERK1/2 and 96.9% (31/32) of tumors has lower phospho-AKT1/2/3 compared to matched mucosa, irrespective of KRAS mutation status and tumor stage. In contrast, we discovered KRAS-dependent SOX9 upregulation in 28 of the 31 (90.3%) tumors. CPTAC phosphoproteomics data similarly showed significantly lower phospho-ERK1/2 levels in tumor compared to matched mucosa. Analysis of transcriptome data from TCGA and GEO series GSE95132 also showed no activation of RAF/MEK/ERK signaling in CRC tumors. These data indicate that the pursue of targeted therapy inhibiting RAF/MEK/ERK and PI3K/Akt signaling is unlikely to be effective in sporadic CRC and possibly harmful as phospho-ERK1/2 are highly expressed in the matched mucosa suggesting a role in normal colonic homeostasis. The widespread use of RAF/MEK/ERK or PI3K/Akt signaling downregulation as a biomarker in drug testing on CRC cell lines needs to be re-evaluated. The data suggest further that SOX9 could be an alternative effector and biomarker of KRAS signaling. Citation Format: Peh Yean Cheah, Kuen Kuen Lam, Choong Leong Tang, Emile Tan, Siew Heng Wong. ERK/AKT pathways may be the wrong effectors for KRAS signaling inhibition in colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6192.