PD-010 - Erlotinib attenuates bevacizumab-mediated activation of EGFR-survival signaling in CRC models independent of KRAS status providing a rational basis...

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Anti-Cancer Agents & Biologic Therapy
Biomarkers
Basic Science
Colon Cancer
Rectal Cancer
Presenter A. Larsen
Citation Annals of Oncology (2015) 26 (suppl_4): 101-107. 10.1093/annonc/mdv234
Authors A. Larsen1, A. De Gramont2, T. André3, B. Chibaudel4, A. Bouygues5, P. Mesange1, C. Tournigand6, D. Muller7, A. Savina8
  • 1INSERM and UPMC, Paris/FR
  • 2Institut Hospitalier Franco-Britannique, Levallois-Perret/FR
  • 3Hopital Saint-Antoine, Paris/FR
  • 4Institut Franco-Britannique, Levallois-Perret/FR
  • 5Laboratory Of Cancer Biology And Therapeutics, Centre de Recherche Saint-Antoine, Paris/FR
  • 6Hôpital Henri Mondor, Créteil/FR
  • 7Cancer Biology and Therapeutics; Centre de Recherche Saint-Antoine; INSERM U938 and Université Pierre et Marie Curie, Paris/FR
  • 8Scientific Partnerships Roche, Boulogne-Billancourt/FR

Abstract

Introduction

We have recently shown that EGFR- and VEGF(R)-targeted small molecules showed synergistic activity in colorectal cancer (CRC) models refractory to combinations of monoclonal antibodies independent of KRAS status. We here wished to determine the activity of bevacizumab in combination with erlotinib and to elucidate the molecular basis for the activity of the combination.

Methods

Three human CRC xenograft models, SW48 (KRAS wt, bevacizumab sensitive), HT-29 (KRAS wt, bevacizumab resistant) and SW620 (KRAS mutant, bevacizumab sensitive) were established in nude mice. Animals were treated with bevacizumab and erlotinib, alone or in combination, and the influence on tumor growth, and the presence of activated EGFR was determined by immunohistochemistry followed by quantitative image analysis. Tumor levels of amphiregulin were determined by ELISA.

Results

Combinations of bevacizumab and erlotinib were significantly more active than bevacizumab alone for all three xenograft models. Quantitative IHC analysis showed that bevacizumab activated EGFR in the tumor cells as well as in the tumor-associated endothelial cells which was attenuated by erlotinib. There is extensive feed-back regulation between EGFR and its ligands including amphiregulin. Accordingly, the erlotinib-bevacizumab combination reduced the levels of amphiregulin in the tumors. Receptor tyrosine kinases mediate multiple downstream signaling pathways that may be integrated at the level of mTORC1, the mammalian target of rapamycin (mTOR) complex 1, and can be measured by tumor levels of Ser240/Ser244-phosphorylated S6 (pS6). Bevacizumab increased pS6 levels which were attenuated by erlotinib, independently of KRAS status.

Conclusion

We here show that combinations of bevacizumab and erlotinib are significantly more active than bevacizumab alone in CRC models with different KRAS status and bevacizumab sensitivity. These findings strongly indicate that EGFR-directed monoclonal antibodies and EGFR-directed small molecule do not have the same limitations with respect to KRAS status. The findings reported here provided the rational basis for the GERCOR phase III DREAM trial which showed increased overall survival of patients with mCRC treated with combinations of erlotinib and bevacizumab in maintenance therapy compared to bevacizumab alone, independent of KRAS status.