Optimized EGFR Blockade Strategies in EGFR Addicted Gastroesophageal Adenocarcinomas

Abstract

Purpose: Gastric and gastroesophageal adenocarcinomas (GEA) represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced GEA is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced GEA treated with anti-EGFR agents. Experimental Design: We performed analyses on 4 cohorts: IRCC (570 patients), FMI (9397 patients), COG (214 patients) and INT (206 patients). Preclinical trials were conducted in patientderived xenografts (PDXs). Results: The analysis of different GEA patient cohorts suggests that EGFR amplification drives aggressive behaviour and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy number gain and that co-amplification of other receptor tyrosine kinases or KRAS is associated with worse response. Pre-clinical trials performed on EGFR-amplified GEA PDX models revealed that the combination of an EGFR monoclonal antibody and an EGFR tyrosine kinase inhibitor was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR amplified non-responding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, co-treatment 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 monoclonal antibody 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.

State-of-the-Art of Monoclonal Antibodies for the Treatment of Gastric Cancer

“…Nevertheless, novel translational research and experimental preclinical data showed a positive correlation between cetuximab response and high EGFR expression/ amplification, which occur in 3-4% of all cases, and let investigator rethink on how to optimize the treatment strategy. In fact, a recent study conducted in PDX xenopatien models has confirmed that EGFR inhibitors may be active in EGFR-addicted gastric adenocarcinoma with EGFR copynumber gain 87 and may serve as springboard for future research to identify potentially actionable targets and resistance mechanisms.…”

“Sandwich” Strategy to Intensify EGFR Blockade by Concurrent Tyrosine Kinase Inhibitor and Monoclonal Antibody Treatment in Highly Selected Patients

“…EGFR amplification predicts aggressive biological behavior and poor prognosis. Preclinical trials performed on PDX models with EGFR -amplified gastroesophageal adenocarcinoma revealed that the cetuximab and lapatinib/erlotinib combination still results in a deep and durable response ( 58 ). Similarly, in a study evaluating the biliary tract cancer cell line HuCCT1 ( in vitro cell proliferation inhibition and apoptosis promotion) and pancreatic cancer cell line Panc430 xenografts, tumor growth in vivo was significantly decreased with combined therapy (gefitinib/erlotinib and cetuximab) ( 44 ).…”

Molecularly Targeted Therapies for Gastric Cancer. State of the Art

“…Unfortunately, phase II trials have shown that these therapies have limited efficacy [22,23]. Recently, Maron et al and Corso et al identified a subpopulation of GC patients presenting a high level of EGFR amplification, which is responsive to anti-EGFR drugs [24,25]. They also identified mechanisms of resistance to EGFR-targeted drugs, such as TKR activation, KRAS mutation/amplification, and TSC2 inactivation [25].…”

“…More recently, a preclinical trial on PDXs allowed a TSC2 mutation leading to increased resistance to EGFR inhibition to be identified. The pharmacological inhibition of TSC2 was positively tested with everolimus, which was able to overcome the resistance and to reestablish the sensitivity to EGFR inhibition [25].…”