EZH2 inhibition confers PIK3CA-driven lung tumors enhanced sensitivity to PI3K inhibition

Fan Chen, Jinpeng Liu, Xiulong Song, Tanner J. DuCote, Aria L. Byrd, Chi Wang, Christine F. Brainson

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Members of the PI3K signaling pathway, especially PIK3CA, the gene encoding the catalytic subunit of the PI3K complex, are highly mutated and amplified in various cancer types, including non-small cell lung cancer. Although PI3K inhibitors have been used in clinics for follicular lymphoma and chronic lymphocytic leukemia, no agents targeting PI3K aberrations in lung cancer have been approved by the FDA so far. In this study, we observed that PIK3CA-E545K, the most common mutation in lung cancer, harbored a modest induction of stem-like properties in lung epithelial cells, and drove development of adenocarcinoma autochthonously when paired with p53 loss in a murine mouse model. We also found that PIK3CA-mutant of amplified lung cancer cells were sensitive to EZH2 inhibition. EZH2 inhibition synergized with PI3K inhibition in human cancer cells in vitro and worked together efficiently in vivo. Mechanistically, EZH2 inhibition cooperated with PI3K inhibition to produce a more potent suppression of phospho-AKT downstream of PI3K. This study suggests a promising combination therapy to combat lung cancers with PIK3CA mutation or amplification. Both copanlisib, the PI3K inhibitor, and tazemetostat, the EZH2 inhibitor, are FDA-approved, which should enhance the clinical translation of this work.

Original languageEnglish
Pages (from-to)151-160
Number of pages10
JournalCancer Letters
Volume524
DOIs
StatePublished - Jan 1 2022

Bibliographical note

Funding Information:
This work was supported in part by NCI K22 CA201036, Kentucky Lung Cancer Research Program, V Foundation Scholar Award, American Cancer Society Institutional Research Grant IRG-85-001-25 , NCI R01 CA237643 , NIGMS P20 GM121327-03 , American Cancer Society Research Scholar Grant 133123-RSG-19-081-01-TBG and American Association for Cancer Research-Bayer Innovation and Discovery Grant (CFB) , NIEHS T32 5T32ES007266-30 (TJD and ALB) and NHLBI F31 HL151111-01 (ALB). This research was also supported by the Biostatistics & Bioinformatics Shared Resource Facility, Biospecimen Procurement & Translational Pathology Shared Resource Facility and Flow Cytometry & Immune Monitoring Shared Resource Facility of the University of Kentucky Markey Cancer Center ( P30CA177558 ). We also thank D. Gilbreath in the Markey Cancer Center Research Communications Office for graphic designs.

Publisher Copyright:
© 2021

Keywords

  • Combination therapy
  • EZH2
  • Epigenetic therapy
  • Lung cancer
  • PI3K

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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