Michael Erb, PhD, The Scripps Research Institute Webinar

Topic

Targets, tools, and mechanisms for disrupting tumorigenic gene expression with small molecules

Description

Ono Pharma Foundation organizes a webinar where research scientists are given the opportunity to present their research findings and encourage scientific exchanges to accelerate advancements in the field and promote open scientific dialogue.

Time

August 29, 2022 Aug 29, 2022 5:00 - 6:00pm PT [8:00 - 9:00pm ET]

Registration

Moderator: Michael A. Erb, Ph.D., Assistant Professor of Chemistry, The Scripps Research Institute

Webinar title: Targets, tools, and mechanisms for disrupting tumorigenic gene expression with small molecules.

Abstract: The coordinated and dynamic control of gene expression is fundamental to specifying and maintaining cell type, state, and function. Alterations to transcriptional programs are a hallmark feature of tumorigenesis with gene regulatory proteins encoded by some of the most frequently altered genes in human cancers. Our laboratory is broadly interested in studying the transcriptional mechanisms of cancer pathogenesis and identifying unique vulnerabilities created by dysregulated gene control. Here, we will showcase our efforts to identify, drug, and study these vulnerabilities using forward genetics, discovery chemistry, and transcriptional genomics – briefly highlighting specific breakthroughs from our lab that illuminate new opportunities to target chromatin reader proteins (ENL/AF9), lysine acetyltransferases, and the NuRD complex.

Presenters:

Talk 1

Tim Bishop is a fifth-year PhD student at Scripps Research working with Michael Erb, where he studies response and resistance to inhibitors of acetyl-lysine writers and readers in AML. Before pursuing his PhD studies, he performed his undergrad training and worked as a technician in the lab of Stephen Small at New York University, where he studied the transcriptional networks that control pattern formation in the early embryonic development of Drosophila melanogaster.

Metabolic control of response to histone acetyltransferase inhibition

Acetyl-CoA-competitive histone acetyltransferase (HAT) inhibitors have garnered attention as potential cancer therapeutics and the first clinical trial for this class is ongoing (NCT04606446). Despite broad enthusiasm for these targets, notably including CBP/p300 and KAT6A/B, the potential mechanisms of therapeutic response and evolved drug resistance remain poorly understood. By modelling acquired drug resistance to a CBP/p300 HAT inhibitor with a forward genetic selection we identified dysregulation of coenzyme A (CoA) metabolism as a facile driver of resistance to HAT inhibitors. Specifically, drug resistance selected for mutations in PANK3, a pantothenate kinase that controls the rate limiting step in CoA biosynthesis. These mutations prevent negative feedback inhibition, resulting in drastically elevated concentrations of intracellular acetyl-CoA, which directly outcompetes drug-target engagement. This not only impacts the activity of structurally diverse CBP/p300 HAT inhibitors, but also agents related to an investigational KAT6A/B inhibitor that is currently in Phase-1 clinical trials. We further validated these results using a genome-scale CRISPR/Cas9 loss-of-function genetic modifier screen, which identified additional gene-drug interactions between HAT inhibitors and the CoA biosynthetic pathway. Top hits from the screen included the phosphatase, PANK4, which negatively regulates CoA production and therefore suppresses sensitivity to HAT inhibition upon knockout, as well as the pantothenate transporter, SLC5A6, which enhances sensitivity. Altogether, this work uncovers CoA plasticity as an unexpected but universal liability of anti-cancer HAT inhibitors and will therefore buoy future efforts to optimize the efficacy of this new class of drug targets.

Talk 2

Yuxiang Zhang is a fifth-year PhD student in the Scripps Research’s graduate program in the Erb lab. His work focuses on investigating the role of transcriptional co-regulators in cancer pathogenesis. Before pursuing his PhD studies, Yuxiang performed his undergraduate training in Professor Zhongying Zhao’s laboratory in Hong Kong Baptist University, where he studied the hybrid incompatibility between nematode species. Following his undergraduate studies, he further pursued MRes training at Imperial College London with Dr. Nikolai Windbichler, Professor Gloria Rudenko, and Dr. Robert Weinzierl.

Targeting the NuRD complex in cancer through HDAC1/2 synthetic lethality 

Synthetic lethality is used as a framework in cancer biology to describe genes that are only essential in the presence of certain tumor-associated alterations. As drug targets, these gene products promise a high therapeutic window, since normal cells do not depend on them for survival. By examining the collection of CRISPR/Cas9 essentiality screens performed in human cancer cell lines (the Cancer Dependency Map) for lineage-restricted vulnerabilities, we revealed the reciprocal synthetic lethality between HDAC1 and HDAC2 in neuroblastoma and multiple myeloma. Mechanistically, we showed that depletion of HDAC2 by genetic perturbation or proteolysis targeting chimera (PROTAC) in HDAC1-deficient neuroblastoma cells destabilizes the HDAC1/2-containing nucleosome repositioning and deacetylase (NuRD) complex, which further exploits the selective dependencies on NuRD subunits including MBD3 and MTA3. As a result, this compromises the regulation of chromatin compaction, super-enhancer-regulated transcription, and inhibits tumor growth in vitro and in vivo. Therefore, we found targeting HDAC1/2 synthetic lethality with selective degradation renders complex-specific disruption and presents as a potential effective therapeutic strategy.

 

Aug 29, 2022 in Pacific Time (US and Canada)

Ono Pharma Foundation organizes a webinar where research scientists are given the opportunity to present their research findings and encourage scientific exchanges to accelerate advancements in the field and promote open scientific dialogue.