Abstract 1822: HER2/PIK3CAH1047R transgenic tumors develop acquired resistance to triple therapy with trastuzumab, pertuzumab, and PI3K inhibitors via multiple mechanisms

Abstract

Abstract The HER2 (ERBB2) oncogene is amplified in 20-25% of breast cancers and is associated with poor patient outcome. Activating mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), occur in ∼30% of breast cancers. HER2 amplification and PIK3CA mutations often co-occur in breast cancer. Aberrant activation of the PI3K pathway correlates with a diminished response to HER2-directed therapies. We previously generated a conditional transgenic mouse model of HER2-overexpressing (HER2+), PIK3CAH1047R-mutant breast cancer. We showed that PIK3CAH1047R accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers and generates resistance to FDA-approved combinations of anti-HER2 therapies (Hanker et al. PNAS 2013). HER2+/PIK3CA tumor growth was inhibited by treatment with the HER2 antibodies trastuzumab and pertuzumab in combination with the pan-PI3K inhibitor BKM120 (TPB). We sought to discover mechanisms of acquired resistance to the triple therapy by long-term treatment of established HER2+/PIK3CA tumors. We utilized tumor transplants derived from two HER2+/PIK3CA transgenic mice, #564 and #635. Tumor transplants from model 564 were initially growth inhibited by TPB, but did not regress. A subset of 564 transplants (3/11) resumed growth in the presence of continuous TPB therapy. Resistance was maintained following passaging in mice and tumors were cross-resistant to trastuzumab/pertuzumab/BYL719, a p110α-specific inhibitor. P-AKT remained suppressed in resistant tumors, whereas P-ERK was elevated. All transplants (n=9) from model 635 regressed to a volume of <100 mm3 within 6 weeks of treatment. All tumors recurred within 2 months; 2 tumors continued growth when re-treated with TPB. Unlike the 564 resistant tumors, P-AKT was restored in the 635 resistant tumors, while short-term TPB treatment strongly inhibited P-AKT in the 635 tumors. TPB-resistant tumor 635-2 expressed p95 HER2, which was not detected in untreated tumors. In contrast, HER2 expression was significantly reduced in TPB-resistant tumor 635-3. We are currently performing whole-exome sequencing on TPB-resistant vs. untreated tumors in order to determine the mechanisms of resistance. Both 564 and 635 TPB-resistant tumor transplants displayed resistance to the antibody-drug conjugate trastuzumab-DM1, despite maintenance of HER2 overexpression. These early data suggest that multiple mechanisms may contribute to resistance to dual HER2 blockade in combination with PI3K inhibitors. In parallel, we are currently establishing human HER2+, PIK3CA-mutant cell lines resistant to TPB. We speculate that a similar heterogeneity of mechanisms of acquired resistance may occur in different HER2+/PIK3CA-mutant metastases in patients. Citation Format: Ariella B. Hanker, Christian D. Young, Thomas P. Stricker, Rebecca S. Cook, Carlos L. Arteaga. HER2/PIK3CAH1047R transgenic tumors develop acquired resistance to triple therapy with trastuzumab, pertuzumab, and PI3K inhibitors via multiple mechanisms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1822. doi:10.1158/1538-7445.AM2014-1822