Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A
Silvana Mourón, María J. Bueno, Aňa Lluch, Luís Manso, Isabel Calvo, Javier Cortés, José Á. García-Sáenz, Miguel Gil‐Gil, Noelia Martínez-Jáñez, Juan V. Apala, Eduardo Caleiras, Pilar Ximénez‐Embún, Javier Muñoz, Lucía González‐Cortijo, Raquel Murillo, Rodrigo Sánchez-Bayona, Juan Miguel Cejalvo, Gonzalo Goméz-López, Coral Fustero‐Torre, Sergio Sabroso‐Lasa, Núria Malats, Mario Martínez-López, A. Moreno, Diego Megı́as, Marcos Malumbres, Rámón Colomer, Miguel Quintela-Fandiño
Abstract
Precision oncology research is challenging outside the contexts of oncogenic addiction and/or targeted therapies. We previously showed that phosphoproteomics is a powerful approach to reveal patient subsets of interest characterized by the activity of a few kinases where the underlying genomics is complex. Here, we conduct a phosphoproteomic screening of samples from HER2-negative female breast cancer receiving neoadjuvant paclitaxel (N = 130), aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 11 candidate biomarkers through 2 independent patient sets (N = 218) allowed the identification of a subgroup of patients characterized by high levels of CDK4 and filamin-A who had a 90% chance of achieving a pCR in response to paclitaxel. Mechanistically, CDK4 regulates filamin-A transcription, which in turn forms a complex with tubulin and CLIP-170, which elicits increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allows the identification of explainable factors for predicting response to paclitaxel.