Abstract PS5-29: Insights into the molecular underpinnings of the mevalonate pathway-YAP/TAZ-driven anti-HER2 therapy resistance in HER2+ breast cancer (BC)

Background. We recently reported that the biosynthetic mevalonate (MVA) pathway that produces cholesterol and isoprenoid intermediates, regulates the YAP/TAZ (Y/T) transcriptional co-activators to promote resistance to treatment regimens that effectively inhibit HER2 signaling in HER2+ BC. We further showed that the mTORC1 complex and survivin protein, which contribute to HER2-elicited oncogenic signaling in HER2-driven BC cells, are alternatively activated by the MVA pathway-Y/T axis in anti-HER2 therapy resistant cell models. Of note, other recent reports also showed that increased Y/T activity enables resistant cells to proliferate when other oncogenic pathways (e.g., RAS, EGFR, and FGFR) were effectively inhibited. Here, we sought to further determine the molecular underpinnings of MVA-Y/T axis-driven anti-HER2 therapy resistance to discover novel therapeutic targets and predictive biomarkers for HER2+ BC.Methods. SKBR3 HER2+ BC parental (P) cells and their lapatinib plus trastuzumab (LT) resistant (LTR) derivatives with sustained HER2 inhibition were treated with the MVA pathway inhibitor simvastatin (Sim), with or without the MVA metabolite to rescue Sim’s inhibitory effects. P and LTR cells were also transfected with control or combined Y/T siRNAs. The transcriptomes of all treatment groups were assessed by RNA-seq. Integrative bioinformatics analyses were used to identify differentially expressed (DE) genes and gene sets with functional annotations in LTR vs. P cells upon different interventions.Results. We found that cell cycle and cell proliferation processes were among the top common DE molecular signatures preferentially downregulated (DN) in LTR vs. P cells by both Sim and Y/T knockdown (KD). The top common genes preferentially DN in LTR vs. P cells include the cell cycle regulatory genes CDCA3 and ERCC6L, and the nucleotide metabolism genes TYMS and RRM2. Interestingly, 20% of the genes preferentially DN in LTR vs. P cells by Sim or Y/T KD were predicted to be direct Y/T transcriptional targets based on previously reported ChIP-seq data (PMID: 26258633). Of the Y/T-dependent genes, a significant enrichment of Sim-repressed genes was observed in both P and LTR cells (P = 1.2e-115 and P = 5.5e-138, respectively). The proportion of these enriched genes was higher in LTR vs. P cells (61% vs. 29%). Of note, we found that the global inhibited genes in LTR cells upon Sim or Y/T KD were significantly enriched for the genes DN by short-term LT treatment in P cells (P Citation Format: Vidyalakshmi Sethunath, Xiaoyong Fu, Pamela L Luna, Sarmistha Nanda, Martin Shea, Jamunarani Veeraraghavan, Carmine De Angelis, Huizhong Hu, Chad Shaw, Mothaffar Rimawi, C. Kent Osborne, Rachel Schiff. Insights into the molecular underpinnings of the mevalonate pathway-YAP/TAZ-driven anti-HER2 therapy resistance in HER2+ breast cancer (BC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-29.