Therapeutic Targeting of NSD2 in Lung Adenocarcinoma

摘要

ABSTRACT Our overarching goal is to evaluate the therapeutic potential and mechanism-of-action of the epigenetic regulatory factor NSD2 in lung adenocarcinoma (LUAD). Lung cancer is the most common cause of cancer- related mortality in the United States and worldwide, leading to over a 1.8 million deaths each year. LUAD is its most common histological type of lung cancer. While new targeted and immunotherapies have improved median survival for LUAD patients, unfortunately, improvement in outcomes over the past 20 years has been incremental. Thus, there is great interest in identifying novel factors that might cooperate with the canonical oncogenic pathways that drive LUAD with the notion that a therapeutic strategy hitting multiple pathways will mitigate potential drug toxicity by lowering the overall dose needed for each medicine and in parallel combat resistance development. A central hypothesis to be tested here is that the clinically actionable and histone lysine 36 (H3K36) di-methyltransferase enzyme NSD2 is such a factor. In preliminary work we found that NSD2 promotes aggressive malignant tumor progression and rapid lethality in a classis LUAD mouse model. In our proposal, we will investigate the molecular, epigenetic, cellular, and in vivo role of NSD2-H3K36me2 axis in lung cancer and directly test the efficacy of NSD2-targeted therapy using a first-in-class NSD2 inhibitor and state-of- the-art pre-clinical models of LUAD. In Aim 1 we investigate the role of NSD2 in lung cancer pathogenesis. We have developed a KRASG12C- driven NSD2 tunable mouse lung cancer model to investigate the function and mechanism of action of elevated or depleted NSD2 activity in LUAD initiation, progression, metastasis, and intratumoral heterogeneity. In Aim 2 we evaluate therapeutic efficacy of NSD2 inhibition using a first-in-class potent inhibitor of NSD2. We will utilize genetic models such as LUAD driven by KRASG12C mutations and multiple patient derived LUAD xenografts to test anti-tumor efficacy of NSD2 inhibition as a single agent and as part of combination therapies. Together, this work will be the first to evaluate the therapeutic potential and mechanism-of-action of NSD2 in LUAD.