YAP1-mediated CDK6 Activation Confers Radiation Resistance in Esophageal Cancer - Rationale for the combination of YAP1 and CDK4/6 inhibitors in Esophageal Cancer

Purpose: Esophageal cancer (EC) is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in EC. Deregulation of both molecules may be responsible for therapy resistance. Experimental Design: Expression of YAP1 and CDK6 were examined in EC cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in EC cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacological and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects in vitro and in vivo. Results: YAP1 expression was positively associated with CDK6 expression in resistant EC tissues and cell lines. YAP1 overexpression upregulated CDK6 expression, transcription, and promoted radiation resistance; whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation as well as sensitized radiation resistant/YAP1^high EC cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 inhibited expression of YAP1 and sensitized resistant EC cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. Additionally, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced EC cell growth, CSC population (ALDH1⁺ and CD133⁺), sensitized cells to irradiation and showed a strong anti-tumor effect in vivo against radiation resistant EC cells. Conclusions: Our results document that a positive crosstalk of YAP1 and CDK6 confers radiation resistance to EC cells. Targeting both YAP1 and CDK6 pathways could be novel therapeutic strategies to overcome resistance in EC.

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