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EZH2 inhibition confers PIK3CA-driven lung tumors enhanced sensitivity to PI3K inhibition
Fan Chen1, Jinpeng Liu2, Xiulong Song1
1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA.
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.
Insights
Targeting PIK3CA mutations in lung cancer shows promise. Combining PI3K and EZH2 inhibitors effectively suppresses tumor growth and offers a potential new therapy for lung cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The PI3K signaling pathway, particularly PIK3CA, is frequently altered in cancers like non-small cell lung cancer.
- While PI3K inhibitors exist for other leukemias, none are FDA-approved for lung cancer.
- PIK3CA mutations and amplifications are common drivers in lung adenocarcinoma.
Purpose of the Study:
- To investigate the role of PIK3CA mutations in lung cancer development.
- To explore therapeutic strategies targeting PIK3CA-altered lung cancers.
- To evaluate the efficacy of combining PI3K and EZH2 inhibition.
Main Methods:
- Utilized a murine model to study PIK3CA-E545K mutation and p53 loss in lung adenocarcinoma development.
- Assessed the sensitivity of PIK3CA-mutant lung cancer cells to EZH2 inhibition.
- Conducted in vitro and in vivo studies to evaluate combination therapy with PI3K and EZH2 inhibitors.
Main Results:
- The PIK3CA-E545K mutation induced stem-like properties and promoted adenocarcinoma development in mice.
- PIK3CA-mutant lung cancer cells showed sensitivity to EZH2 inhibition.
- Combination therapy of PI3K and EZH2 inhibitors demonstrated synergistic suppression of tumor growth in vitro and in vivo.
- Mechanistically, combined inhibition potently suppressed downstream phospho-AKT signaling.
Conclusions:
- Combination therapy targeting PI3K and EZH2 presents a promising strategy for PIK3CA-altered lung cancers.
- The use of FDA-approved drugs (copanlisib and tazemetostat) facilitates clinical translation.
- This approach offers a potential new treatment avenue for non-small cell lung cancer.
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