| First Author | Chen F | Year | 2022 |
| Journal | Cancer Lett | Volume | 524 |
| Pages | 151-160 | PubMed ID | 34655667 |
| Mgi Jnum | J:314035 | Mgi Id | MGI:6810259 |
| Doi | 10.1016/j.canlet.2021.10.010 | Citation | Chen F, et al. (2022) EZH2 inhibition confers PIK3CA-driven lung tumors enhanced sensitivity to PI3K inhibition. Cancer Lett 524:151-160 |
| abstractText | 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. |
