DARPP-32 and t-DARPP in the development of resistance to anti-HER2 agents. Pre-clinical evidence from the STEP study.

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.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FSDL: Ipsen and Novartis, outside the submitted work. AB: Pfizer, Roche, Lilly, Novartis, Msd, Seagen, Gilead and Daiichi Sankyo, outside the submitted work. DS: Amgen, Astellas, Astrazeneca, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, outside the submitted work. GDA: Novartis, Amgen, Eli Lilly, outside the submitted work. CM: Bayer, Roche, AstraZeneca and Daiichi-Sankyo, outside the submitted work. P.V.: Pfizer, Novartis, Eisai, Daiichi Sankyo and Eli Lilly, outside of the manuscript under consideration L.P.: Novartis and Pfizer, outside of the manuscript under consideration. No potential conflicts of interest were disclosed for other authors
(Copyright © 2023. Published by Elsevier Inc.)