Unbiased screening reveals that blocking exportin 1 overcomes resistance to PI3Kα inhibition in breast cancer

Abstract

TO THE EDITOR: Targeting PI3K is a promising approach for cancer therapy, and the PI3Kα-selective inhibitor alpelisib has been approved for breast cancer treatment. However, the development of acquired resistance poses a significant clinical challenge. Loss of PTEN and activation of mTOR, CDK4/6, or PIM have been reported to mediate acquired resistance to alpelisib. The mechanisms leading to resistance to PI3Kα inhibitors appear to be different under different circumstances, and the aforementioned strategies may be beneficial for a particular group of patients. New strategies to overcome acquired resistance in a broad spectrum of patients need to be discovered. CYH33 is a novel PI3Kα-selective inhibitor in phase I clinical trials (NCT03544905) and exhibits potent activity against breast cancer in preclinical settings. Given that the structure of CYH33 distinct from that of alpelisib, the mechanisms of acquired resistance to CYH33 may be unlike those of alpelisib. To monitor the occurrence of resistance to CYH33, we established CYH33-resistant cell lines named