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Abstract 3245: Genes associated with Src-Met driven resistance of head & neck cancers to EGFR-PI3K cotargeting


 Background: In recent years, oncology research has led to the discovery of targeted therapies aimed at specific genetic abnormalities unique to cancer cells. In particular, the overexpression of epidermal growth factor receptor (EGFR) and constitutive activation of the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) pathway are common aberrations in head and neck cancer. However, intrinsic and acquired resistance are continuously posing challenges to success. Previously, we reported that the combination of EGFR inhibitor erlotinib with PI3K inhibitor BKM120 had synergistic effects that induced efficient apoptosis in a panel of head and neck cancer cell lines, but some cells were still resistant. The purpose of the current study is to understand the mechanism of resistance to EGFR and PI3-K co-targeting.
 Hypothesis: Src-Met signaling confers apoptosis resistance to EGFR and PI3K cotargeting by regulating downstream genes expresiion.
 Methods: Apoptosis was measured by annexin V-PE staining. Western blotting and qPCR were used for measuring the expression of proteins and mRNA, respectively. RNASeq was conducted from RNA samples treated with (Erlotinib + BKM120) ± dasatinib (Src inhibitor)/crizotinib(Met inhibitor).
 Results: Biochemical studies revealed that JHU022 cells, which were resistant to the combination treatment, had an overactivation of c-Met receptor tyrosine kinase that was regulated by Src kinases. Pharmacological or genetic inactivation of both Met or Src kinase sensitized this cell line to apoptosis induced by EGFR and PI3K co-targeting. RNA-Seq analysis identified that a total of 291 genes were modulated (2-folds) by both crizotinib and dasatinib. Pathway enrichment suggested that many of these genes were associated with cell cycle, DNA replication, and cellular response to DNA damage. CPA4 was identified as the most downregulated gene and GDF15 as one of the top upregulated genes.
 Conclusions: SRC-Met signaling confers resistant to EGFR and PI3K cotargeting by modulating genes associated with cell cycle, DNA replication, and cellular response to DNA damage.
 Citation Format: Adeoluwa A. Adeluola, A.R.M. Ruhul Amin. Genes associated with Src-Met driven resistance of head & neck cancers to EGFR-PI3K cotargeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3245.