Overcoming the Resistance of CDK4/6 Inhibitors in Breast Cancer Cells
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Acquired resistance is a major impediment for treatment of breast cancer (BC) patients by CDK4/6 inhibitors (CDK4/6i). FDA has approved three CDK4/6 inhibitors to treat patients with advanced estrogen receptor-positive (ER+) BC. Although these drugs have significantly improved the progression-free survival of patients, many patients eventually develop resistance to these drugs. It is urgent to elucidate the mechanism of resistance and develop new approaches to overcome the resistance. In this study, using high throughput screen we have identified a ITK inhibitor that could effectively overcome the CDK4/6i resistance of MCF-7 cells. Further investigation demonstrated that ITK inhibitor overcomes resistance due to its off targeting on RET (Rearranged during Transcription) and DDR1 (discoidin domain receptor 1) genes. Significantly, we found that both RET and DDR1 are highly expressed in MCF-7 resistant (PR) cells to CDK4/6i. Thus, our studies not only elucidate a novel mechanism regulating CDK4/6i resistance, but also identify a potential approach to treat the resistance by targeting RET and DDR1.
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