Abstract 2622: Targeting Rac/Cdc42 GTPases to overcome HER2-targeted therapy resistance

Abstract

Abstract Breast cancer is the most common cancer in women. Breast cancer is categorized by the overexpression (or lack thereof) of estrogen receptors (ER+/-), progesterone receptors (PR+/-) or human epidermal growth factor 2 receptors (HER2+/-). Specifically, HER2+ breast cancer is one of the most aggressive subtypes, comprising ~20% of all cases. Overexpression of the HER2 receptor leads to active downstream signaling that results in cell proliferation and metastasis. Clinically, this problem has been tackled by targeting the HER2 receptor with antibodies (e.g., Trastuzumab, Pertuzumab) and (or) tyrosine kinase inhibitors (TKIs; e.g., Lapatinib). However, patients may present with intrinsic or acquired resistance to these therapies. Molecular mechanisms of resistance to HER2 targeted therapy include activating mutations, alterations in downstream effectors, and compensation from other growth factor receptors. The active signaling sequelae from such mechanisms converge on the activation of guanine nucleotide exchange factors (GEFs) that regulate the GTPases Rac and Cdc42. These GTPases are critical for cell migration/invasion and have been correlated with poor prognosis in breast cancer patients. Therefore, targeting the activation of Rac/Cdc42 is a rational strategy to overcome HER2-targeted therapy resistance. Previously, we characterized the dual Rac/Cdc42 inhibitor MBQ-167 with IC50s of 103nM and 78nM for Rac and Cdc42, respectively. Our objective is to test MBQ-167 as an alternative to overcome HER2-targeted therapy resistance. To test the hypothesis that MBQ-167 will overcome HER2 therapy resistance, metastatic trastuzumab resistant HER2 overexpressing cells were treated with vehicle or individual or combined Trastuzumab and MBQ-167. Rac activity was determined by pulldown assays for active (GTP-bound) Rac, and viability was tested by MTT assays. Additionally, we measured apoptosis via caspase 3/7 activity and western blotted for the active signaling sequelae downstream of Rac. MBQ-167 reduced Rac activity and downstream signaling, as well as cell viability with a GI50 of 78nM after 72 hours, while caspase activity was increased after 24 hours of treatment. The results presented herein show the utility of the Rac/Cdc42 inhibitor MBQ-167 in overcoming HER2-targeted therapy resistance. Citation Format: Miciely Cristal Aponte Reyes, Luis E. Velazquez Vega, Suranganie Dharmawardhane. Targeting Rac/Cdc42 GTPases to overcome HER2-targeted therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2622.