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

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

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. dyu@mdanderson.org.
  • 11 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mhung@cmu.edu.tw.
  • 12 Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. mhung@cmu.edu.tw.
  • 13 Department of Biotechnology, Asia University, Taichung, Taiwan. mhung@cmu.edu.tw.
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.

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