Open AccessKRAS mutation‐independent downregulation of MAPK/PI3K signaling in colorectal cancer
Author(s) -
Lam Kuen Kuen,
Tang Choong Leong,
Tan Emile,
Wong Siew Heng,
Cheah Peh Yean
Publication year - 2022
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.13163
Subject(s) - kras , colorectal cancer , pi3k/akt/mtor pathway , cancer research , carcinogenesis , protein kinase b , downregulation and upregulation , mapk/erk pathway , biology , cancer , signal transduction , gene , genetics
KRAS is a gatekeeper gene in human colorectal tumorigenesis. KRAS is ‘undruggable’; hence, efforts have been diverted to inhibit downstream RAF/MEK/ERK and PI3K/Akt signaling. Nevertheless, none of these inhibitors has progressed to clinical use despite extensive trials. We examined levels of phospho‐ERK1/2(T202/Y204) and phospho‐Akt1/2/3(S473) in human colorectal tumor compared to matched mucosa with semi‐quantitative near‐infrared western blot and confocal fluorescence immunohistochemistry imaging. Surprisingly, 75.5% (25/33) of tumors had lower or equivalent phospho‐ERK1/2 and 96.9% (31/32) of tumors had lower phospho‐Akt1/2/3 compared to matched mucosa, irrespective of KRAS mutation status. In contrast, we discovered KRAS ‐dependent SOX9 upregulation in 28 of the 31 (90.3%) tumors. These observations were substantiated by analysis of the public domain transcriptomics The Cancer Genome Atlas (TCGA) and NCBI Gene Expression Omnibus (GEO) datasets and proteomics Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset. These data suggest that RAF/MEK/ERK and PI3K/Akt signaling are unlikely to be activated in most human colorectal cancer.