Selective NSD2 Inhibition Reveals an Epigenetic Dependency of KRAS-Driven Cancers

NSD2, through generation of the epigenetic modification histone H3 di-methylated at lysine 36 (H3K36me2), is a candidate convergent downstream effector of oncogenic KRAS-signaling. However, whether NSD2 targeting represents a therapeutic vulnerability of KRAS-driven cancers is unknown. Here, we characterize a first-in-class, clinical grade small molecule catalytic NSD2 inhibitor (NSD2i) series and find pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven pre-clinical cancer models. NSD2i inhibits NSD2 potently, with single digit nM IC50 values, and shows high selectively for NSD2 versus NSD1, NSD3, and other similar enzymes. Structural analyses reveal the molecular basis of NSD2i specificity for NSD2, which includes S-adenosylmethionine (SAM)-competitive binding and catalytic disruption via a dual-channel obstruction mechanism. Proteo-epigenomic and single cell strategies in pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) samples support a model in which durable NSD2i exposure reverses H3K36me2-driven pathologic chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail KRAS-regulated and oncogenic-associated gene expression programs. Accordingly, NSD2i treatment inhibits PDAC and LUAD cell viability and patient-derived xenograft tumor growth. Further, NSD2 inhibition, which is well tolerated in vivo, is equally effective as KRAS inhibition (sotorasib) treatment in prolonging survival in advanced stage autochthonous KRASG12C-driven PDAC and LUAD mouse tumor models. Moreover, in these models, NSD2 inhibition and sotorasib co-treatment synergize to confer sustained survival with extensive tumor nodule regression and elimination. Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in KRAS-driven cancers and provides a mechanistic rationale for testing NSD2i-KRAS inhibition combination therapies in the clinic.