epz-6438 and Lung-Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Benzamides; Biphenyl Compounds; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Humans; Lung Neoplasms; Mice; Morpholines; Mutation; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Quinazolines; Signal Transduction; Xenograft Model Antitumor Assays

The primary endpoint of disease control rate at 12 weeks was met with a partial response in two patients.

Topics: Benzamides; Biphenyl Compounds; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Morpholines; Pleural Neoplasms; Pyridones

Trimethylation of lysine 27 and dimethylation of lysine 9 of histone-H3 catalyzed by the histone methyltransferases EZH2 and G9a impede gene transcription in cancer. Our human bronchial epithelial (HBEC) pre-malignancy model studied the role of these histone modifications in transformation. Tobacco carcinogen transformed HBEC lines were characterized for cytosine DNA methylation, transcriptome reprogramming, and the effect of inhibiting EZH2 and G9a on the transformed phenotype. The effects of targeting EZH2 and G9a on lung cancer prevention was assessed in the A/J mouse lung tumor model.. Carcinogen exposure induced transformation and DNA methylation of 12-96 genes in the four HBEC transformed (T) lines that was perpetuated in malignant tumors. In contrast, 506 unmethylated genes showed reduced expression in one or more HBECTs with many becoming methylated in tumors. ChIP-on-chip for HBEC2T identified 327 and 143 genes enriched for H3K27me3 and H3K9me2. Treatment of HBEC2T and HBEC13T with DZNep, a lysine methyltransferase inhibitor depleted EZH2, reversed transformation, and induced transcriptional reprogramming. The EZH2 small molecule inhibitor EPZ6438 also affected transformation and expression in HBEC2T, while a G9a inhibitor, UNC0642 was ineffective. Genetic knock down of EZH2 dramatically reduced carcinogen-induced transformation of HBEC2. Only DZNep treatment prevented progression of hyperplasia to adenomas in the NNK mouse lung tumor model through reducing EZH2 and affecting the expression of genes regulating cell growth and invasion.. These studies demonstrate a critical role for EZH2 catalyzed histone modifications for premalignancy and its potential as a target for chemoprevention of lung carcinogenesis.

Topics: Adenosine; Adenosylhomocysteinase; Animals; Benzamides; Biphenyl Compounds; Cell Proliferation; Chromatin Assembly and Disassembly; CpG Islands; DNA Methylation; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Epigenesis, Genetic; Epithelial Cells; Female; Histone Code; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones; Humans; Lung Neoplasms; Mice; Morpholines; Neoplasms; Phenotype; Pyridones; Transcriptome