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HDAC6 as a Prognostic Factor and Druggable Target in HER2-Positive Breast Cancer
Michela Cortesi1, Sara Bravaccini1, Sara Ravaioli1
1IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy.
Background:
Adjuvant trastuzumab is the standard of care for HER2+ breast cancer (BC) patients. However, >50% of patients become resistant. This study aimed at the identification of the molecular factors associated with disease relapse and their further investigation as therapeutically exploitable targets.
Methods:
Analyses were conducted on formalin-fixed paraffin-embedded tissues of the primary tumors of relapsed (cases) and not relapsed (controls) HER2+ BC patients treated with adjuvant trastuzumab. The nCounter Human Breast Cancer Panel 360 was used. Logistic regression and partitioning around medoids were employed to identify the genes associated with disease recurrence. Cytotoxicity experiments using trastuzumab-resistant cell lines and a network pharmacology approach were carried out to investigate drug efficacy.
Results:
A total of 52 patients (26 relapsed and 26 not relapsed) were analyzed. We found that a higher expression of HDAC6 was significantly associated with an increased risk of recurrence, with an adjusted OR of 3.20 (95% CI 1.38-9.91, p = 0.016). Then, we investigated the cytotoxic activity of the selective HDAC6 inhibitor Nexturastat A (NextA) on HER2+ cell lines, which were both sensitive and trastuzumab-resistant. A sub-cytotoxic concentration of NextA, combined with trastuzumab, showed a synergistic effect on BC cell lines. Finally, using a network pharmacology approach, we identified HSP90AA1 as the putative molecular candidate responsible for the synergism observed in vitro.
Conclusions:
Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance.
Insights
This study identifies HDAC6 as a predictor of recurrence in HER2+ breast cancer (BC) patients treated with trastuzumab. Combining HDAC6 inhibitors with trastuzumab shows promise for overcoming drug resistance in BC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Adjuvant trastuzumab is standard for HER2+ breast cancer (BC).
- Over 50% of patients develop resistance to trastuzumab.
- Identifying molecular factors for relapse is crucial for new therapeutic strategies.
Purpose of the Study:
- Identify molecular factors associated with disease relapse in HER2+ BC patients.
- Investigate these factors as potential therapeutic targets.
Main Methods:
- Analyzed tumor tissues from relapsed and non-relapsed HER2+ BC patients.
- Utilized nCounter Human Breast Cancer Panel 360 for gene expression analysis.
- Employed logistic regression and network pharmacology to identify recurrence-associated genes and drug efficacy.
Main Results:
- Higher HDAC6 expression correlated with increased recurrence risk (OR=3.20, p=0.016).
- HDAC6 inhibitor Nexturastat A (NextA) combined with trastuzumab demonstrated synergistic effects on trastuzumab-resistant HER2+ BC cell lines.
- HSP90AA1 was identified as a potential mediator of this synergism.
Conclusions:
- HDAC6 shows potential as a prognostic factor in HER2+ BC.
- Combination therapy with HDAC6 inhibitors and trastuzumab warrants further investigation for overcoming resistance in HER2+ BC patients.
