Growth suppression of ERBB2-driven breast cancers by p300/CBP inhibition

Abstract

Breast cancer, which affects 1 in 8 women in the US, is divided into four major subtypes based on the overexpression or lack of expression of three different molecular markers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2, also referred to as ERBB2). About 20% of all newly diagnosed breast cancer cases are ERBB2-positive, and these breast cancer patients tend to have poorer prognosis with lower overall survival compared to hormone receptor-positive breast cancer (ACS, 2020). Although there are several anti-ERBB2 drugs available there are still many patients at both the early and metastatic stages of ERBB2-positive breast cancer that do not respond, or more commonly, relapse with disease resistance to the first line of anti-ERBB2 treatments (Baselga et al., 2017). Additional targeted anti-ERBB2 treatments are therefore needed to complement current ERBB2 therapeutic options. Using a panel of ERBB2-positive human breast cancer cell lines to model all ERBB2-positive breast cancers, the Benz lab has been pursuing evidence that the regulation of ERBB2 overexpression is in large part dependent on ERBB2 transcript stability. The Benz lab has previously demonstrated that ERBB2 mRNA stability is regulated by the p300 histone acetyltransferase (p300HAT) and class-1 histone deacetylases (HDACs) including HDAC-1/2. With this mechanistic insight, the Benz lab has launched a study comparing the ERBB2 mRNA destabilizing effects of the p300/ CREB binding protein (CBP) HAT inhibitor, A-485, since both agents appear to accelerate the decay of ERBB2 mRNA in a number of ERBB2-positive human breast cancer cell line models. Because A-485 has more tolerable side effects compared to FK228, this study further investigates HATi, A-485 efficacy by combining it with several breast cancer drugs. After a series of failed tries to find a synergistic drug that works with A-485, we found Taxol as a candidate. In addition, given that the current clinical approach in treating ERBB2-positive breast cancers is to combine a pathway-targeted anti-ERBB2 agent with a microtubule-stabilizing taxane chemotherapeutic like paclitaxel (Taxol), this project is focused on trying to advance new preclinical rationale for combining A-485 with taxol as a novel and alternative treatment approach for women with ERBB2-positive breast cancers.