DARPP-32 and t-DARPP in the development of resistance to anti-HER2 agents. Pre-clinical evidence from the STEP study
Giulia Bon1, Eriseld Krasniqi2, Manuela Porru3
1Department of Research, Cellular Network and Molecular Therapeutic Target Unit, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
Abstract:
The therapeutic scenario of Human Epidermal Growth Factor Receptor 2 positive advanced breast cancer (ABC) has been recently enriched by a number of innovative agents, which are reshaping treatment sequence. While randomized trials have documented an advantage in terms of efficacy, for the newly available agents we lack effectiveness and tolerability evidence from the real-world setting. Similarly, the identification of predictive biomarkers might improve clinical decision. We herein describe the outline of a prospective/retrospective study which aims to explore the optimal sequence of treatment in HER2+, pertuzumab pre-treated ABC patients treated in II line with anti-HER2 agents in clinical practice. As part of the pre-clinical tasks envisioned by the STEP study, in vitro cell models of resistance were exploited to investigate molecular features associated with reduced efficacy of HER2 targeting agents at the transcript level. The aggressive behavior of resistant cell populations was measured by growth assessment in mouse models. This approach led to the identification of DARPP-32 and t-DARPP proteins as possible predictive biomarkers of efficacy of anti-HER2 agents. Biomarkers validation and the clinical goals will be reached through patients' inclusion into two independent cohorts, i.e., the prospective and retrospective cohorts, whose setup is currently ongoing.
Insights
This study investigates optimal treatment sequences for Human Epidermal Growth Factor Receptor 2 positive advanced breast cancer (ABC). It identifies DARPP-32 and t-DARPP proteins as potential biomarkers for anti-HER2 agent efficacy.
Area of Science:
- Oncology
- Pharmacology
- Biomarker Discovery
Background:
- The treatment landscape for HER2-positive advanced breast cancer (ABC) is evolving with new agents.
- Real-world data on the effectiveness and tolerability of these novel therapies are limited.
- Predictive biomarkers are needed to guide clinical decisions in HER2-positive ABC.
Purpose of the Study:
- To explore optimal treatment sequences in HER2-positive, pertuzumab pre-treated ABC patients receiving second-line anti-HER2 agents.
- To identify predictive biomarkers for the efficacy of anti-HER2 agents in clinical practice.
- To validate potential biomarkers in prospective and retrospective patient cohorts.
Main Methods:
- Utilized in vitro cell models of resistance to investigate molecular features affecting HER2-targeting agent efficacy.
- Assessed the aggressive behavior of resistant cell populations in mouse models.
- Planned inclusion of patients in prospective and retrospective cohorts for biomarker validation.
Main Results:
- Identified DARPP-32 and t-DARPP proteins as potential predictive biomarkers for anti-HER2 agent efficacy.
- Investigated molecular features at the transcript level associated with reduced efficacy.
- Characterized the aggressive behavior of resistant cell populations.
Conclusions:
- DARPP-32 and t-DARPP show promise as predictive biomarkers for anti-HER2 therapies in HER2-positive ABC.
- Further validation in clinical cohorts is ongoing to confirm biomarker utility.
- Understanding resistance mechanisms is crucial for optimizing treatment strategies in advanced breast cancer.
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