Faculty, Staff and Student Publications
Publication Date
10-1-2022
Journal
Nature Cancer
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.
Keywords
Animals, Female, Humans, Mice, Anaplastic Lymphoma Kinase, Antineoplastic Agents, Biomarkers, Breast Neoplasms, Cyclin-Dependent Kinase 9, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Positive Transcriptional Elongation Factor B, Tyrosine, Ubiquitin-Protein Ligases, United States
DOI
10.1038/s43018-022-00438-2
PMID
36253486
PMCID
PMC9586872
PubMedCentral® Posted Date
10-3-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons