Selective NSD2 Inhibition Reveals an Epigenetic Vulnerability of KRAS-Driven Cancers [RNA-Seq]

NSD2, through generation of the epigenetic modification histone H3 di-methylated at lysine 36 (H3K36me2) is a candidate convergent downstream effector of oncogenic signaling. However, whether selective inhibition of NSD2 enzymatic activity at chromatin can serve as an effective cancer therapy is unknown. Here, we characterize a first-in-class, clinical grade small molecule catalytic NSD2 inhibitor (NSD2i) series and find that pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven pre-clinical cancer models. NSD2i potently inhibits NSD2 with single digit nM IC50 values and high selectivity over NSD1, NSD3, and other methyltransferases. Structural analyses reveal the molecular basis of NSD2i specificity for NSD2 includes S-adenosylmethionine (SAM)-competitive binding and catalytic disruption via a binary-channel obstruction mechanism. Proteo-epigenomic and single-cell strategies in pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) samples support a model in which sustained 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 inhibits PDAC and LUAD cell viability and patient-derived xenograft tumor growth. Further, NSD2i, which is well-tolerated in vivo, prolongs survival in advanced-stage autochthonous KRASG12C-driven PDAC and LUAD mouse tumor models nearly as effectively as KRAS inhibition with sotorasib. Moreover, in these models, NSD2i synergizes with sotorasib 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 inhibitor combination therapies in the clinic.