AXL - a new player in resistance to HER2 blockade.

HER2 is a driver in solid tumors, mainly breast, oesophageal and gastric cancer, through activation of oncogenic signaling pathways such as PI3K or MAPK. HER2 overexpression associates with aggressive disease and poor prognosis. Despite targeted anti-HER2 therapy has improved outcomes and is the current standard of care, resistance emerge in some patients, requiring additional therapeutic strategies. Several mechanisms, including the upregulation of receptors tyrosine kinases such as AXL, are involved in resistance. AXL signaling leads to cancer cell proliferation, survival, migration, invasion and angiogenesis and correlates with poor prognosis. In addition, AXL overexpression accompanied by a mesenchymal phenotype result in resistance to chemotherapy and targeted therapies. Preclinical studies show that AXL drives anti-HER2 resistance and metastasis through dimerization with HER2 and activation of downstream pathways in breast cancer. Moreover, AXL inhibition restores response to HER2 blockade in vitro and in vivo. Limited data in gastric and oesophageal cancer also support these evidences. Furthermore, AXL shows a strong value as a prognostic and predictive biomarker in HER2+ breast cancer patients, adding a remarkable translational relevance. Therefore, current studies enforce the potential of co-targeting AXL and HER2 to overcome resistance and supports the use of AXL inhibitors in the clinic.

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Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Juan M. Cejalvo reports speakers' fees from Novartis and Pfizer Inc. and travel expenses from Roche, Lilly, Novartis and Pfizer Inc. outside the submitted work. Dr. Prat has a patent (HER2DX) licensed to Reveal Genomics, has a patent (WO 2018/103834) licensed to Reveal Genomics, and is an equity stockholder in Reveal Genomics. Hehas declared personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo, travel, accommodations, and expenses paid by Daiichi Sankyo, research funding from Nanostring Technologies, Roche and Novartis, consulting/advisory role for Nanostring Technologies, Roche, Novartis, Pfizer, Oncolytics Biotech, Amgen, Lilly, MSD, PUMA and Daiichi Sankyo, Inc. outside the submitted work. Joquin Arribas has received research funds from Roche, Byondis, Menarini and Molecular Partners and consultancy honoraria from Menarini and Mnemo. J.A. is inventor of patent applications EP20382457.8, EP 16191933.7, EP 0930183.5, and P200801652.