Abstract 2828: Combining neratinib with trastuzumab deruxtecan to treat HER2;TP53 co-mutated breast cancers

Abstract

Abstract In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in the TP53 gene and patients with these two co-occuring mutations have a lower response rate to neratinib. In order to address this clinical problem, we bred HER2 activating mutant transgenic mice with two different alleles of TP53. We used mice with the TP53 R172H mutation, which is the murine homolog of the human hotspot TP53 R175H mutation, and mice with TP53flox/flox allele, which mimics TP53 truncating mutations seen in human breast cancers. All three H53 genotypes (H53null, H53172/WT, and H53172/null) developed breast cancers faster than H mice, with H53172/null mice developing breast tumors the fastest, at just 6 weeks after adenoviral-Cre injection into the mammary fat pad. We developed organoids from these murine breast cancers and found that all H53 genotype organoids were less sensitive to neratinib compared to H, however, neratinib was able to synergize with trastuzumab deruxtecan (T-DXd), likely through neratinib mediated increased internalization of T-DXd. Prior literature studies suggest TP53 mutant cancer cells may have therapeutic vulnerabilities to the topoisomerase 1 (Top1) inhibitors. Organoids from all three H53 genotypes were sensitive to the Top1 inhibitor, exatecan. H53172/WT behaved like H organoids with G1 phase cell cycle arrest and induction of p21 expression after exatecan treatment. In contrast, H53null and H53172/null failed to induce p21 and arrested at late-S/G2 phase. Additional animal experiments with these H53 genotypes are in progress and results will be presented at the AACR Annual Meeting. Abbreviation Genotype Median tumor formation (weeks) Neratinib IC50 (nM) Neratinib +T-DXd H HER2V777L 28 10 Not determined H53null HER2V777L;TP53flox/flox 10 240 Synergy H53172/WT HER2V777L;TP53R172H/WT 11 100 Synergy H53172/null HER2V777L;TP53R172H/flox 6 150 Synergy Citation Format: Xiaoqing (Cathy) Cheng, Maureen Highkin, Jacob Hsia, Julie L. Prior, Ian S. Hagemann, Ron Bose. Combining neratinib with trastuzumab deruxtecan to treat HER2;TP53 co-mutated breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2828.