Targeting the ALK-CDK9-Tyr19 kinase cascade sensitizes ovarian and breast tumors to PARP inhibition via destabilization of the P-TEFb complex.
Yu-Yi ChuMei-Kuang ChenYongkun WeiHeng-Huan LeeWeiya XiaYing-Nai WangClinton YamJennifer L HsuHung-Ling WangWei-Chao ChangHirohito YamaguchiZhou JiangChunxiao LiuChing-Fei LiLei NieLi-Chuan ChanYuan GaoShao-Chun WangJinsong LiuShannon Neville WestinSanghoon LeeAnil K SoodLiuqing YangGabriel N HortobagyiDihua YuMien-Chie HungPublished in: Nature cancer (2022)
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.
Keyphrases
- dna repair
- dna damage
- advanced non small cell lung cancer
- cell cycle
- poor prognosis
- drug administration
- oxidative stress
- gene expression
- endothelial cells
- tyrosine kinase
- type diabetes
- epidermal growth factor receptor
- dna methylation
- adipose tissue
- protein kinase
- induced apoptosis
- risk assessment
- human health
- endoplasmic reticulum stress