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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Precision oncology faces challenges in complex genomic cases.
• Phosphoproteomics can identify patient subsets based on kinase activity.
• Identifying predictive biomarkers for neoadjuvant chemotherapy is crucial.

Purpose of the Study:

• To identify candidate biomarkers for paclitaxel sensitivity in HER2-negative breast cancer.
• To validate identified biomarkers in independent patient cohorts.
• To elucidate the mechanism underlying paclitaxel response.

Main Methods:

• Phosphoproteomic screening of 130 HER2-negative breast cancer patients receiving neoadjuvant paclitaxel.
• Validation of 11 candidate biomarkers in 2 independent patient sets (N=218).
• Mechanistic studies involving CDK4, filamin-A, tubulin, and CLIP-170 interactions.

Main Results:

• A subgroup of patients with high CDK4 and filamin-A levels showed a 90% pathological complete response (pCR) rate to paclitaxel.
• CDK4 was found to regulate filamin-A transcription.
• A mechanism involving filamin-A, tubulin, and CLIP-170 was elucidated, enhancing paclitaxel's effect on microtubules.

Conclusions:

• Phosphoproteomics is a powerful tool for discovering predictive biomarkers in complex cancers.
• CDK4 and filamin-A are promising biomarkers for predicting paclitaxel response in HER2-negative breast cancer.
• The identified mechanism provides a molecular basis for personalized paclitaxel treatment strategies.