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Adaptive Resistance to Chemotherapy, A Multi-FAK-torial Linkage.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2018 Apr; Vol. 17 (4), pp. 719-723. - Publication Year :
- 2018
-
Abstract
- Oncogenes provide tumor cells with a growth and survival advantage. Directed therapies targeted to oncogenic mutations (such as BRAF V600E) are part of effective late-stage melanoma treatment. However, tumors with BRAF V600E mutations, in approximately 10% of colorectal cancer, are generally treatment-insensitive. Research has identified various "feedback" mechanisms that result in BRAF signal pathway reactivation in response to BRAF inhibition. Herein, we highlight key findings from Chen and colleagues (this issue) showing that integrin-associated focal adhesion kinase (FAK) activation selectively occurs in BRAF V600E-mutant colorectal cancer cells in response to pharmacological BRAF inhibition. FAK activation results in elevated β-catenin protein levels, β-catenin nuclear localization, and increased gene transcription. Small-molecule inhibitors of β-catenin or FAK synergize with vemurafenib BRAF inhibitor to prevent BRAF V600E colorectal cancer cell proliferation in vitro and xenograft tumor growth in mice. This study complements findings linking FAK to β-catenin in intestinal tumorigenesis, resistance to radiotherapy, and cancer stem cell survival. Thus, FAK activation may occur as a frequent tumor cell "adaptive resistance" mechanism. Although FAK ( PTK2 ) is not mutated in most cancers, targeting FAK activity in combinational approaches may limit tumor cell escape mechanisms and enhance durable responses to treatment. Mol Cancer Ther; 17(4); 719-23. ©2018 AACR .<br /> (©2018 American Association for Cancer Research.)
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 17
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Report
- Accession number :
- 29610281
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-17-1177