Targeting the ALK-CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex.

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.

• Authors: 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 Hortobagyi, Dihua Yu, Mien-Chie Hung
• Journal: Nature cancer (Nat Cancer) Vol. 3 Issue 10 Pg. 1211-1227 (10 2022) ISSN: 2662-1347 [Electronic] England
• PMID: 36253486 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Anaplastic Lymphoma Kinase
• Antineoplastic Agents
• Biomarkers
• CDK9 protein, human
• Cyclin-Dependent Kinase 9
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases
• Positive Transcriptional Elongation Factor B
• Tyrosine
• Ubiquitin-Protein Ligases

Topics

• Animals
• Female
• Humans
• Mice
• Anaplastic Lymphoma Kinase (metabolism)
• Antineoplastic Agents (pharmacology)
• Biomarkers
• Breast Neoplasms (drug therapy)
• Cyclin-Dependent Kinase 9 (metabolism)
• Poly(ADP-ribose) Polymerase Inhibitors (metabolism)
• Poly(ADP-ribose) Polymerases (metabolism)
• Positive Transcriptional Elongation Factor B
• Tyrosine (chemistry, metabolism)
• Ubiquitin-Protein Ligases (drug effects, metabolism)
• United States