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Stephen J Murphy

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-12 - EGFR Therapy in ASCL1 Positive Lung Adenocarcinoma (ID 14211)

      16:45 - 18:00  |  Author(s): Stephen J Murphy

      • Abstract


      Greater than 40% of lung adenocarcinomas (LUAD) contain no known driver mutations from point mutation or structural variance analysis. Recently, we discovered that 15-20% of LUAD have abnormally high levels of ASCL1, a key regulator of neuroendocrine differentiation in the lung. ASCL1 in these tumors orchestrates the expression of a network of genes that affect the behavior of tumors and their microenvironments and provide opportunities for treatment that has largely been understudied. The goal of this study was to explore potential therapeutic options in these tumors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Bioinformatics analyses used public and internally generated expression data from LUAD. In vitro co-immunoprecipitation and cytotoxicity assays were used to determine the interaction between proteins and the sensitivity to EGFR blockers gefitinib and lapatinib. These drugs were also tested in patient derived xenograft (PDX) models from cisplatin resistant brain met LUAD with (A+AD) and without (A-AD) ASCL1 expression.

      4c3880bb027f159e801041b1021e88e8 Result

      Our data demonstrated that ASCL1 acts upstream of RET and promotes chronic over-expression of the oncogene in A+AD. In vitro experiments revealed a strong interactions between wild type EGFR and RET in A+AD which rendered these tumors vulnerable to treatment by EGFR blockers. Furthermore, while EGFR inhibitors blocked tumor growth in the A+AD PDX model, they were completely ineffective in the A-AD PDX model. EGFR therapy also markedly changed key regulators of the tumor microenvironment in favor of anti-tumor immunity. Analysis of TCGA data identified some overlap between A+AD and other LUAD subtypes, such as KRAS or EGFR mutant tumors. Further meta-analysis in a compendium of microarray data in stage-1 LUAD from multiple institutions demonstrated that high expression of wild type RET was significantly associated with a poor overall survival. Furthermore, high expression of EGFR (or its ligand TGFA) and RET imparted an aggressive phenotype in A+AD with overall survival similar to small cell lung cancer. Notably, EGFR, TGFA, and RET did not have any prognostic value in A-AD.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data provide strong evidence that patients with A+AD may benefit from a multipronged treatment strategy that include EGFR therapy even in the absence of mutations in EGFR.