Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A

S. Mouron, M. J. Bueno, A. Lluch, L. Manso, I. Calvo, J. Cortes, J. A. Garcia-Saenz, M. Gil-Gil, N. Martinez-Janez, J. V. Apala, E. Caleiras, Pilar Ximénez-Embún, J. Muñoz, L. Gonzalez-Cortijo, R. Murillo, R. Sánchez-Bayona, J. M. Cejalvo, G. Gómez-López, C. Fustero-Torre, S. Sabroso-Lasa, N. Malats, M. Martinez, A. Moreno, D. Megias, M. Malumbres, R. Colomer and M. Quintela-Fandino ()
Additional contact information
S. Mouron: Breast Cancer Clinical Research Unit Centro Nacional de Investigaciones Oncológicas – CNIO
M. J. Bueno: Breast Cancer Clinical Research Unit Centro Nacional de Investigaciones Oncológicas – CNIO
A. Lluch: Hospital Clínico Universitario
L. Manso: Hospital Universitario 12 de Octubre
I. Calvo: Anderson Cancer Center Madrid
J. Cortes: International Breast Cancer Center Quiron Group
J. A. Garcia-Saenz: Hospital Clinico San Carlos
M. Gil-Gil: Catala d’Oncologia-IDIBELL L’Hospitalet de
N. Martinez-Janez: Hospital Universitario Ramon y Cajal
J. V. Apala: Breast Cancer Clinical Research Unit Centro Nacional de Investigaciones Oncológicas – CNIO
E. Caleiras: Histopathology Unit Centro Nacional de Investigaciones Oncológicas – CNIO
Pilar Ximénez-Embún: Proteomics Unit Centro Nacional de Investigaciones Oncológicas – CNIO
J. Muñoz: Proteomics Unit Centro Nacional de Investigaciones Oncológicas – CNIO
L. Gonzalez-Cortijo: Hospital Universitario Quironsalud
R. Murillo: Hospital Universitario Quironsalud
R. Sánchez-Bayona: Hospital Universitario 12 de Octubre
J. M. Cejalvo: Hospital Clínico Universitario
G. Gómez-López: Bioinformatics Unit Centro Nacional de Investigaciones Oncológicas – CNIO
C. Fustero-Torre: Bioinformatics Unit Centro Nacional de Investigaciones Oncológicas – CNIO
S. Sabroso-Lasa: Genetic & Molecular Epidemiology Group Centro Nacional de Investigaciones Oncológicas – CNIO
N. Malats: Genetic & Molecular Epidemiology Group Centro Nacional de Investigaciones Oncológicas – CNIO
M. Martinez: Hospital Universitario 12 de Octubre
A. Moreno: Hospital Universitario de Fuenlabrada
D. Megias: Confocal Microscopy Unit Centro Nacional de Investigaciones Oncológicas – CNIO
M. Malumbres: Cell Division and Cancer Group Centro Nacional de Investigaciones Oncológicas – CNIO
R. Colomer: Hospital Universitario La Princesa
M. Quintela-Fandino: Breast Cancer Clinical Research Unit Centro Nacional de Investigaciones Oncológicas – CNIO

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35065-z

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