Optimized EGFR blockade strategies in EGFR addicted gastroesophageal adenocarcinomas

Simona Corso, Filippo Pietrantonio, Maria Apicella, Cristina Migliore, Daniella Conticelli, Annalisa Petrelli, Laura D'Errico, Stefano Durando, Daniel Moya-Rull, Sara E. Bellamo, Stefano Ughetto, Maurizio Degiuli, Rossella Reddavid, Uberto Fumagalli Romario, Stefano de Pascale, Giovanni Sgroi, Emanuele Rausa, Gian Luca Baiocchi, Sarah Molfino, Giovanni de ManzoniMaria Bencivenga, Salvatore Siena, Andrea Sartore-Bianchi, Federica Morano, Salvatore Corallo, Michele Prisciandaro, Maria Di Bartolomeo, Annunziata Gloghini, Silvia Marsoni, Antonino Sottile, Anna Sapino, Caterina Marchio, Asa Dahle-Smith, Zosia Miedzybrodzka, Jessica Lee, Siraj M. Ali, Jeffrey S. Ross, Brian M. Alexander, Vincent A. Miller, Russell Petty, Alexa B. Schrock, Silvia Giordano (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    11 Citations (Scopus)
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    Abstract

    Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.

    Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).

    Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.

    Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors.

    Original languageEnglish
    Pages (from-to)3126-3140
    Number of pages15
    JournalClinical Cancer Research
    Volume27
    Issue number11
    Early online date4 Feb 2021
    DOIs
    Publication statusPublished - 1 Jun 2021

    Keywords

    • EGFR
    • targeted therapy
    • gastric and gastroesophageal cancer
    • drug resistance
    • mTOR

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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