Abstract
Background: Cancers with copy-gain drug-target genes are excellent candidates for targeted therapy. In order to search for new predictive marker genes, we investigated the correlation between sensitivity to targeted drugs and the copy gain of candidate target genes in NCI-60 cells. Methods: For eight candidate genes showing copy gains in NCI-60 cells identified in our previous study, sensitivity to corresponding target drugs was tested on cells showing copy gains of the candidate genes. Results: Breast cancer cells with Focal Adhesion Kinase (FAK)-copy-gain showed a significantly higher sensitivity to the target inhibitor, FAK inhibitor 14 (F14). In addition, treatment of F14 or FAK-knockdown showed a specific apoptotic effect only in breast cancer cells showing FAK-copy-gain. Expression-profiling analyses on inducible FAK shRNA-transfected cells showed that FAK/AKT signaling might be important to the apoptotic effect by target inhibition. An animal experiment employing a mouse xenograft model also showed a significant growth-inhibitory effect of F14 on breast cancer cells showing FAK-copy-gain, but not on those without FAK-copy-gain. Conclusion: FAK-copy-gain may be a predictive marker for FAK inhibition therapy in breast cancer.
Highlights
Cancer remains an incurable disease worldwide with a high mortality rate, owing, to a significant extent, to its unresponsiveness or resistance to chemotherapeutic agents
We found that eight drug-target genes including Focal Adhesion Kinase (FAK), MYC, EGFR, ERBB2, FGFR1, MET, IGF1R, and MAP2K2 gained copies in NCI-60 cells
We found that breast cancer cells with FAK-copy-gain showed higher sensitivity to FAK inhibitor 14 (F14), a FAK inhibitor, which is known to inhibit cancer cell growth via its inhibition of FAK phosphorylation at Y397 [11]
Summary
Cancer remains an incurable disease worldwide with a high mortality rate, owing, to a significant extent, to its unresponsiveness or resistance to chemotherapeutic agents. There are several predictive markers that are employed to select candidate cancer patients for targeted therapy. Copy gains of drug-target genes have proved the most important predictive markers for chemotherapy in cancer patients. In order to search for new predictive marker genes, we investigated the correlation between sensitivity to targeted drugs and the copy gain of candidate target genes in NCI-60 cells. Results: Breast cancer cells with Focal Adhesion Kinase (FAK)-copy-gain showed a significantly higher sensitivity to the target inhibitor, FAK inhibitor 14 (F14). Treatment of F14 or FAK-knockdown showed a specific apoptotic effect only in breast cancer cells showing FAK-copy-gain. An animal experiment employing a mouse xenograft model showed a significant growth-inhibitory effect of F14 on breast cancer cells showing FAK-copy-gain, but not on those without FAK-copy-gain. Conclusion: FAK-copy-gain may be a predictive marker for FAK inhibition therapy in breast cancer
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