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Abstract 1075: AXL is a potential druggable target in trastuzumab resistance in HER2+ breast cancer patients

Introduction HER2+ correlates with aggressive phenotype and poor prognosis. The use of several antiHER2 drugs has dramatically improved prognosis and survival of HER2+ breast cancer (BC) patients. However, ≈20% of these patients will present resistance to antiHER2 therapies and relapse. The purpose of this study is to explore the role of AXL in antiHER2 treatment resistance and its potential as a druggable biomarker in HER2+ BC. Methods We generated 2 trastuzumab (T) resistant models from a HER2+ BC patient. The first one was a PDX derived resistant cell line established by chronic treatment for 6 months with T in vitro (TR1 and TR2). The second resistant model (TR4) was established by chronic treatment with T for 4 months and two serial passages in mice. The prognostic value of AXL was evaluated in primary tumor cohort of HER2+ BC patients treated by standard guidelines (n=51). AXL was also explored in a cohort from PAMELA trial, a neoadjuvant phase II study. Patients were given lapatinib and T for 18 weeks (Luminal-HER2+ patients were additionally given hormonotherapy). Tumor samples were collected at baseline, day 14 and surgery (n= 96). Results PDX resistant cell lines (TR1 and TR2) and resistant tumors (TR4) exhibit upregulation of AXL in comparison to the parental cells (PDX118). In vitro, the combination of an AXL inhibitor (TP-0903) + T resensitized resistant cells to T. In 3D organoids models from TR4, the combination decreased cell number in organoids more than both single agents. In TR4 in vivo model, TP-0903 + T completely abrogate tumor growth for more than 2 months.To validate our preclinical findings, we analyzed the level of AXL in our retrospectively cohort of patients. AXL level was significantly upregulated in patients who relapsed (p Conclusion AXL level was correlated with poor outcome of HER2+ BC patients. On our preclinical models, we showed that combination of TP-0903 and T abrogate tumor growth in acquired resistant models to T in PDXs. We postulate AXL as a promising new therapeutic strategy to overcome resistance to antiHER2 therapies Citation Format: Anna Adam-Artigues, Raimundo Cervera, Enrique Javier Arenas, Fara Braso-Maristany, Alex Martinez-Sabadell, Eduardo Tormo, Cristina Hernando, Maria Teresa Martinez, Soraya Simon, Jesus Poveda, Octavio Burgues, Ana Rovira, Federico Rojo, Joan Albanell, Begona Bermejo, Ana Lluch, Pilar Eroles, Aleix Prat, Joaquin Arribas, Juan Miguel Cejalvo. AXL is a potential druggable target in trastuzumab resistance in HER2+ breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1075.