Optimized EGFR blockade strategies in EGFR addicted gastroesophageal adenocarcinomas

TY - JOUR

T1 - Optimized EGFR blockade strategies in EGFR addicted gastroesophageal adenocarcinomas

AU - Corso, Simona

AU - Pietrantonio, Filippo

AU - Apicella, Maria

AU - Migliore, Cristina

AU - Conticelli, Daniella

AU - Petrelli, Annalisa

AU - D'Errico, Laura

AU - Durando, Stefano

AU - Moya-Rull, Daniel

AU - Bellamo, Sara E.

AU - Ughetto, Stefano

AU - Degiuli, Maurizio

AU - Reddavid, Rossella

AU - Romario, Uberto Fumagalli

AU - Pascale, Stefano de

AU - Sgroi, Giovanni

AU - Rausa, Emanuele

AU - Baiocchi, Gian Luca

AU - Molfino, Sarah

AU - Manzoni, Giovanni de

AU - Bencivenga, Maria

AU - Siena, Salvatore

AU - Sartore-Bianchi, Andrea

AU - Morano, Federica

AU - Corallo, Salvatore

AU - Prisciandaro, Michele

AU - Bartolomeo, Maria Di

AU - Gloghini, Annunziata

AU - Marsoni, Silvia

AU - Sottile, Antonino

AU - Sapino, Anna

AU - Marchio, Caterina

AU - Dahle-Smith, Asa

AU - Miedzybrodzka, Zosia

AU - Lee, Jessica

AU - Ali, Siraj M.

AU - Ross, Jeffrey S.

AU - Alexander, Brian M.

AU - Miller, Vincent A.

AU - Petty, Russell

AU - Schrock, Alexa B.

AU - Giordano, Silvia

N1 - Copyright © 2021, American Association for Cancer Research.

PY - 2021/6/1

Y1 - 2021/6/1

N2 - 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.

AB - 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.

KW - EGFR

KW - targeted therapy

KW - gastric and gastroesophageal cancer

KW - drug resistance

KW - mTOR

U2 - 10.1158/1078-0432.CCR-20-0121

DO - 10.1158/1078-0432.CCR-20-0121

M3 - Article

C2 - 33542076

SN - 1078-0432

VL - 27

SP - 3126

EP - 3140

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 11

ER -