Abstract A039: Carnitine palmitoyltransferase IA: an emerging potential metabolic target to counteract HER2-targeted therapy resistance in HER2-positive breast cancer

Abstract

Abstract HER2 overexpression/amplification (HER2+) occurs in 15-20% of breast cancer (BC) and identifies a clinically aggressive BC subtype. Although the introduction of effective anti-HER2 drugs remarkably improved the prognosis of HER2+ BC patients, primary and acquired tumor resistance to anti-HER2 treatments underscores the need for novel therapies for HER2+ BC patients. Tumor cells exhibit unique metabolic alterations that are responsible for primary or acquired tumor resistance to standard therapies, and which are increasingly emerging as potential targets for novel treatment strategies. In particular, the dysregulation of fatty acid β-oxidation (FAO), a catabolic process that produces energy (ATP and NADPH production) to sustain cancer growth, survival and aggressiveness, is associated with therapy resistance in diverse malignancies including BC. Specifically, carnitine palmitoyltransferase 1A (CPT1A), the key rate-limiting enzyme of mitochondrial FAO, facilitates cancer metabolic adaptation, thus representing a promising target for cancer therapy. In this context, gene set enrichment analysis of profiled matched HER2+ BC samples (n=33) collected before and after trastuzumab-based neo-adjuvant biochemotherapy (trastuzumab plus taxanes) revealed that the Fatty Acids (FA) metabolism gene set was one of the most significantly Hallmark enriched pathway (NES=1.57; FDR=0.0039) in post- compared with pre-treated HER2+ BC samples, implying that trastuzumab plus chemotherapy treatment induces an enhancement of FAO activity. Accordingly, CPT1A transcript levels were found to be inversely associated with lapatinib (L) susceptibility in HER2+ BC cell lines and patient-derived organoids resistant to anti-HER2 therapy versus L-sensitive cell models. Additionally, Seahorse Analysis revealed higher baseline oxidation of the FA palmitate in intrinsically L-resistant HER2+ BC cells as compared with L-sensitive cells, thus supporting the hypothesis that FAO could represent the major lipid metabolic pathway sustaining the energetic needs of HER2+ BC cells resistant to anti-HER2 therapy for survival and growth. Further, the pharmacological dual blockade of HER2 and CPT1A significantly increases cytotoxicity of L-resistant cell models versus single agents, corroborating the candidacy of CPT1A as a potential metabolic vulnerability to be targeted to overcome refractoriness to HER2-targeted therapy in HER2+ BC. Our data support the hypothesis that the inhibition of FAO sensitizes HER2+ BC cells to anti-HER2 drugs, thus representing a potential strategy to overcome drug resistance in HER2+ BC and paving the way to investigate CPT1A inhibitors with anti-HER2 drugs to improve the clinical outcomes of HER2+ BC patients with acquired resistance to standard anti-HER2 therapies. Citation Format: Alma Franceschini, Lorenzo T Castagnoli, Tiziana IINDT Triulzi, Paola Antonia Corsetto, Matteo Dugo, Antonino Belfiore, Andrea Vingiani, Lorena Signati, Serena Mazzucchelli, Fabio Corsi, Francesca Ligorio, Elda Tagliabue, Claudio Vernieri, Serenella M. Pupa. Carnitine palmitoyltransferase IA: an emerging potential metabolic target to counteract HER2-targeted therapy resistance in HER2-positive breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A039.