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Bcl-2 and Bcl-xL mediate resistance to receptor tyrosine kinase-targeted therapy in lung and gastric cancer
| Content Provider | Scilit |
|---|---|
| Author | Jin, Junfei Xiong, Ying Cen, Bo |
| Copyright Year | 2017 |
| Description | Journal: Anti-Cancer Drugs Promising clinical efficacy has been observed with receptor tyrosine kinase inhibitors (TKIs) particularly in lung and gastric cancers with mutations or amplifications in the targeted receptor tyrosine kinases (RTKs). However, the efficacy and the duration of the response to these inhibitors are limited by the emergence of drug resistance. Here, we report treatment of RTK-dependent lung and gastric cancer cell lines with TKIs increased protein levels of Bcl-2 and Bcl-xL. The combination of the Bcl-2 and Bcl-xL inhibitor ABT-263 and TKIs was superior to TKIs alone in reducing cell viability and capacity of resistant colony formation. Furthermore, resistant cells established with exposure of RTK-dependent cells to increasing concentrations of TKIs also express higher levels of Bcl-2 or Bcl-xL compared with their parental cells. The combination of inhibitors of PI3K/AKT, MEK/ERK, and Bcl-2/Bcl-xL effectively reduced the viability of resistant cells and inhibited tumor size in a xenograft model derived from resistant cells by inducing apoptosis. Our results define a generalizable resistance mechanism to TKIs and rationalize inhibition of Bcl-2 and Bcl-xL as a strategy to augment responses and blunt acquired resistance to TKIs in lung and gastric cancer. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659308/pdf |
| Ending Page | 1149 |
| Page Count | 9 |
| Starting Page | 1141 |
| ISSN | 09594973 |
| e-ISSN | 14735741 |
| DOI | 10.1097/cad.0000000000000561 |
| Journal | Anti-Cancer Drugs |
| Issue Number | 10 |
| Volume Number | 28 |
| Language | English |
| Publisher | Ovid Technologies (Wolters Kluwer Health) |
| Publisher Date | 2017-11-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Anti-Cancer Drugs Research and Experimental Medicine Bcl-2, Bcl-xl, Gastric Cancer, Lung Cancer, Molecularly Targeted Therapy, Receptor Tyrosine Kinase, Tyrosine Kinase Inhibitor |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Pharmacology Pharmacology (medical) Oncology |
