An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy.

Autor: Yang M; Department of Surgery & Molecular Medicine, University of South Florida, Tampa General Hospital Cancer Institute, 560 Channelside Drive, Tampa, FL, 33602, USA., Davis TB; Department of Surgery & Molecular Medicine, University of South Florida, Tampa General Hospital Cancer Institute, 560 Channelside Drive, Tampa, FL, 33602, USA., Pflieger L; Precision Genomics Translational Science Center, Intermountain Healthcare, 5026 South State Street, Murray, UT, 84107, USA., Nebozhyn MV; Sharp and Dohme, 770 Sumneytown Pike, Building 53, West Point, P.O. Box 4, Merck, PA, 19486, USA., Loboda A; Sharp and Dohme, 770 Sumneytown Pike, Building 53, West Point, P.O. Box 4, Merck, PA, 19486, USA., Wang H; Department of Surgery & Molecular Medicine, University of South Florida, Tampa General Hospital Cancer Institute, 560 Channelside Drive, Tampa, FL, 33602, USA., Schell MJ; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA., Thota R; Oncology Clinical Program, Intermountain Healthcare, 5026 South State Street, Murray, UT, 84107, USA., Pledger WJ; Department of Surgery & Molecular Medicine, University of South Florida, Tampa General Hospital Cancer Institute, 560 Channelside Drive, Tampa, FL, 33602, USA.; Huntsman Cancer Institute, University of Utah, 2000 Cir of Hope Dr, Salt Lake City, UT, 84112, USA., Yeatman TJ; Department of Surgery & Molecular Medicine, University of South Florida, Tampa General Hospital Cancer Institute, 560 Channelside Drive, Tampa, FL, 33602, USA. yeatman7383@gmail.com.; Huntsman Cancer Institute, University of Utah, 2000 Cir of Hope Dr, Salt Lake City, UT, 84112, USA. yeatman7383@gmail.com.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2022 Mar 10; Vol. 22 (1), pp. 256. Date of Electronic Publication: 2022 Mar 10.
DOI: 10.1186/s12885-022-09344-3
Abstrakt: Background: Over half of colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors, has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms that are not well understood. This study aims to investigate MEK inhibitor-associated resistance signaling and identify subpopulation(s) of CRC patients who may be sensitive to biomarker-driven drug combination(s).
Methods: We classified 2250 primary and metastatic human CRC tumors by consensus molecular subtypes (CMS). For each tumor, we generated multiple gene expression signature scores measuring 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. We carried out correlation, survival and other bioinformatic analyses. Validation analyses were performed in two independent publicly available CRC tumor datasets (n = 585 and n = 677) and a CRC cell line dataset (n = 154).
Results: Here we report a central role of SRC in mediating "bypass"-resistance to MEK inhibition (MEKi), primarily in cancer stem cells (CSCs). Our integrated and comprehensive gene expression signature analyses in 2250 CRC tumors reveal that MEKi-resistance is strikingly-correlated with SRC activation (Spearman P < 10 -320 ), which is similarly associated with EMT (epithelial to mesenchymal transition), regional metastasis and disease recurrence with poor prognosis. Deeper analysis shows that both MEKi-resistance and SRC activation are preferentially associated with a mesenchymal CSC phenotype. This association is validated in additional independent CRC tumor and cell lines datasets. The CMS classification analysis demonstrates the strikingly-distinct associations of CMS1-4 subtypes with the MEKi-resistance and SRC activation. Importantly, MEKi + SRCi sensitivities are predicted to occur predominantly in the KRAS mutant, mesenchymal CSC-like CMS4 CRCs.
Conclusions: 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. We 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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