Targeting the ALK–CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex
Yu‐Yi Chu, Mei‐Kuang Chen, Yongkun Wei, Heng‐Huan Lee, Weiya Xia, Ying‐Nai Wang, Clinton Yam, Jennifer L. Hsu, Hung-Ling Wang, Wei‐Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao‐Chun Wang, Jinsong Liu, Shannon N. Westin, Sanghoon Lee, Anil K. Sood, Liuqing Yang, Gabriel N. Hortobágyi, Dihua Yu, Mien‐Chie Hung
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor growth and improve survival of mice in PARP inhibitor-/platinum-resistant tumor xenograft models. Using human tumor biospecimens, we further demonstrate that phosphorylated ALK (p-ALK) expression is associated with resistance to PARP inhibitors and positively correlated with p-Tyr19-CDK9 expression. Together, our findings support a biomarker-driven, combinatorial treatment strategy involving ALK and PARP inhibitors to induce synthetic lethality in PARP inhibitor-/platinum-resistant tumors with high p-ALK-p-Tyr19-CDK9 expression.