Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2‐Hippo signaling pathway

• Published in: Clinical and translational medicine 2021-08, Vol.11 (8), p.e503-n/a
• Main Authors: Zhang, Yi, He, Long‐Jun, Huang, Lin‐Lin, Yao, Sheng, Lin, Nan, Li, Ping, Xu, Hui‐Wen, Wu, Xi‐Wen, Xu, Jian‐Liang, Lu, Yi, Li, Yan‐Jie, Zhu, Sen‐Lin
• Format: Article
• Language: English
• Subjects: Aged; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Breast cancer; Cancer therapies; CDK4/6 inhibitor; Cell cycle; Cell growth; Cell Line, Tumor; China; Clinical medicine; Committees; Cyclin-Dependent Kinase 4 - drug effects; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 6 - drug effects; Cyclin-Dependent Kinase 6 - genetics; Cyclin-dependent kinases; Disease Models, Animal; DNA methylation; Drug resistance; Female; Flow cytometry; Gastric cancer; Gene expression; Hippo signaling pathway; Hippo Signaling Pathway - drug effects; Hippo Signaling Pathway - genetics; Humans; Investigations; Kinases; Male; Mice; Mice, Nude; Middle Aged; Oncogenes - drug effects; Oncogenes - genetics; PAX6; PAX6 Transcription Factor - drug effects; PAX6 Transcription Factor - genetics; Piperazines - pharmacology; Protein Serine-Threonine Kinases - drug effects; Protein Serine-Threonine Kinases - genetics; Proteins; Pyridines - pharmacology; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Transcription factors; Tumor Suppressor Proteins - drug effects; Tumor Suppressor Proteins - genetics; Tumorigenesis
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.503

Intrinsic resistance to CDK4/6 inhibitors hinders their clinical utility in cancer treatment. Furthermore, the predictive markers of CDK4/6 inhibitors in gastric cancer (GC) remain incompletely described. Here, we found that PAX6 expression was negatively correlated with the response to palbociclib in vitro and in vivo in GC. We observed that the PAX6 expression level was negatively correlated with the overall survival of GC patients and further showed that PAX6 can promote GC cell proliferation and the cell cycle. The cell cycle is regulated by the interaction of cyclins with their partner serine/threonine cyclin‐dependent kinases (CDKs), and the G1/S‐phase transition is the main target of CDK4/6 inhibitors. Therefore, we tested whether PAX6 expression was correlated with the GC response to palbociclib. We found that PAX6 hypermethylates the promoter of LATS2 and inactivates the Hippo pathway, which upregulates cyclin D1 (CCND1) expression. This results in a suppressed response to palbociclib in GC. Furthermore, we found that the induction of the Hippo signaling pathway or treatment with a DNA methylation inhibitor could overcome PAX6‐induced palbociclib resistance in GC. These findings uncover a tumor promoter function of PAX6 in GC and establish overexpressed PAX6 as a mechanism of resistance to palbociclib. PAX6 can promote gastric cancer progression. PAX6 can promote palbociclib in gastric cancer via suppressing Hippo signaling. Induction of the Hippo signaling pathway or treatment with DNA methylation inhibitor could overcome PAX6‐induced palbociclib resistance in gastric cancer.