Optimized EGFR Blockade Strategies in EGFR Addicted Gastroesophageal Adenocarcinomas

Simona Corso, Filippo Pietrantonio, Maria Apicella, Cristina Migliore, Daniela Conticelli, Annalisa Petrelli, Laura D'Errico, Stefania Durando, Daniel Moya-Rull, Sara E. Bellomo, Stefano Ughetto, Maurizio Degiuli, Rossella Reddavid, Uberto Fumagalli, 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

Research output: Contribution to journalArticlepeer-review

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 pages16
JournalClinical Cancer Research
Volume27
Issue number11
Early online date4 Feb 2021
DOIs
Publication statusPublished - 1 Jun 2021

Keywords

  • COPY NUMBER ABERRATIONS
  • GROWTH-FACTOR RECEPTOR
  • GASTRIC-CANCER
  • GENE AMPLIFICATION
  • ACQUIRED-RESISTANCE
  • MET
  • CETUXIMAB
  • TRASTUZUMAB
  • MUTATION
  • ANTIBODY

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