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

  • Nat Cancer. 2022 Oct 17. doi: 10.1038/s43018-022-00438-2.
Yu-Yi Chu  1 ,  Mei-Kuang Chen  1  2 ,  Yongkun Wei  1 ,  Heng-Huan Lee  1 ,  Weiya Xia  1  3 ,  Ying-Nai Wang  1 ,  Clinton Yam  1  2  4 ,  Jennifer L Hsu  1 ,  Hung-Ling Wang  3 ,  Wei-Chao Chang  3 ,  Hirohito Yamaguchi  1  3 ,  Zhou Jiang  1 ,  Chunxiao Liu  1 ,  Ching-Fei Li  1 ,  Lei Nie  1 ,  Li-Chuan Chan  1 ,  Yuan Gao  1  5 ,  Shao-Chun Wang  3 ,  Jinsong Liu  6 ,  Shannon N Westin  7 ,  Sanghoon Lee  8 ,  Anil K Sood  7  9 ,  Liuqing Yang  1 ,  Gabriel N Hortobagyi  4 ,  Dihua Yu  10 ,  Mien-Chie Hung  11  12  13
Affiliations
  • 1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2. UT Health Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
  • 4. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Department of Anatomic Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8. Department of Systems Biology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 9. Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 10. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 11. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 12. Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. [email protected].
  • 13. Department of Biotechnology, Asia University, Taichung, Taiwan. [email protected].
PMID: 36253486 DOI: 10.1038/s43018-022-00438-2
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.

Products