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PI3K activation promotes resistance to eribulin in HER2-negative breast cancer

2021; Springer Nature; Volume: 124; Issue: 9 Linguagem: Inglês

10.1038/s41416-021-01293-1

1532-1827

Albert Gris‐Oliver, Yasir H. Ibrahim, Martín A. Rivas, Celina García-García, Mònica Sánchez-Guixé, Fiorella Ruíz‐Pace, Cristina Viaplana, José Manuel Pérez-García, Antonio Llombart‐Cussac, Judit Grueso, Mireia Parés, Marta Guzmán, Olga Rodríguez, Pilar Antón, Patricia Cozar, María Teresa Calvo, Alejandra Bruna, Joaquı́n Arribas, Carlos Caldas, Rodrigo Dienstmann, Paolo Nucíforo, Mafalda Oliveira, Javier Cortés, Violeta Serra,

Advanced Breast Cancer Therapies

Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance. Resistance to eribulin was evaluated in HER2− BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/AKT pathway. Eleven out of 23 HER2− BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or AKT1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced AKT phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/AKT pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling apoptosis, thus sensitising to eribulin treatment. PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2− BC patients.