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Phosphoproteomic analysis of neoadjuvant breast cancer reveals a subset of patients with increased sensitivity to paclitaxel driven by CDK4 and Filamin A.

ABSTRACT: Precision oncology research is challenging outside 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 conducted a phosphoproteomic screening in a neoadjuvant trial of HER2-negative breast cancer patients (N=130) treated with paclitaxel or paclitaxel plus nintedanib, aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 15 candidate biomarkers through 2 independent patient sets (N=218) allowed finding 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 regulated Filamin-A transcription, which in turn formed a complex with Tubulin and CLIP-170, what elicited increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allowed finding explainable predictive factors for paclitaxel.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Miguel Quintela

LAB HEAD: Miguel Quintela-Fandino

PROVIDER: PXD034355 | Pride | 2022-11-08

REPOSITORIES: Pride

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