Bibliographic Details
| Title: |
An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy |
| Authors: |
Mingli Yang, Thomas B. Davis, Lance Pflieger, Michael V. Nebozhyn, Andrey Loboda, Heiman Wang, Michael J. Schell, Ramya Thota, W. Jack Pledger, Timothy J. Yeatman |
| Source: |
BMC Cancer, Vol 22, Iss 1, Pp 1-21 (2022) |
| Publisher Information: |
BMC, 2022. |
| Publication Year: |
2022 |
| Collection: |
LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| Subject Terms: |
Colorectal cancer, MEK inhibitor, Targeted therapy, SRC, EMT, Cancer stem cell, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| More Details: |
Abstract 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 |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1471-2407 |
| Relation: |
https://doaj.org/toc/1471-2407 |
| DOI: |
10.1186/s12885-022-09344-3 |
| Access URL: |
https://doaj.org/article/b3ce1c0168df4f64b92380ac36065a83 |
| Accession Number: |
edsdoj.b3ce1c0168df4f64b92380ac36065a83 |
| Database: |
Directory of Open Access Journals |
