KAT6A as a novel druggable target for cancer treatment: mechanisms and therapeutic implications in KAT6A-dependent tumors - PROJECT SUMMARY High-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) exhibit shared clinical and genomic characteristics, including poor prognosis, homologous recombination deficiencies, and potential immunoreactivity. These diseases present a pressing and unmet medical need for the identification of new therapeutic targets. Histone acetylation enzymes have emerged as compelling drug targets due to the demonstrated clinical success of histone deacetylase inhibitors in hematological malignancies, affirming the feasibility of this therapeutic approach. Imbalanced histone acetylation, a hallmark of epigenetic alteration in cancer, disrupts genome organization and gene transcription, thereby promoting tumorigenesis. While both histone acetyltransferases (HATs) and histone deacetylases (HDACs) are involved in regulated histone acetylation, HATs are generally associated with accessible chromatin and increased transcription activity, essential for hyperproliferating tumor cells. Consequently, targeting HATs holds promise as a more efficient strategy for cancer treatment. However, the development of HAT-targeting therapy in the clinic has lagged significantly behind HDACi. Although potent and selective HATis with in vivo efficacy in cancer models have been developed at the preclinical stage, the identification and prioritization of specific HAT targets among the 37 distinct HATs in humans have posed challenges. Utilizing a novel systems biology approach developed by our team, we conducted a comprehensive characterization of genes encoding HATs in cancers, leading to the identification of KAT6A as a promising clinical actionable drug target. Preclinical studies have shown the potential of KAT6i as a monotherapy and in combination with FDA-approved drugs in KAT6A-dependent tumors. Notably, potent and selective KAT6is have been successfully developed and are currently undergoing evaluation in phase 1 clinical trial. We hypothesize that KAT6A hyperactivation disrupts the delicate balance of histone acetylation, leading to aberrant genome accessibility and dysregulated transcriptional programs (KAT6A addiction). Therefore, KAT6A serves as a novel therapeutic target in a subset of tumors primarily driven by the recurrent amplification of the KAT6A gene. In this application, we aim to assess the therapeutic potential of newly developed KAT6is as monotherapy and in combination with targeted therapy drugs in preclinical models of HGSOC and TNBC. We have assembled a team of collaborators with added expertise and resources to address the following specific aims: Specific Aim 1: Characterizing the epigenetic changes induced by KAT6i treatment in KAT6A-dependent cancer. Specific Aim 2: Defining the mechanism of action of KAT6i treatment in KAT6A- dependent cancer. Specific Aim 3: Evaluating the therapeutic potential of KAT6i as mono- and combination therapy for cancer. Through these proposed studies, we anticipate providing a strong rationale for KAT6A as a novel drug target for the treatment of cancer.
