Abstract Despite multi-modal treatment intensification, nearly half of children with high-risk neuroblastoma (NBL) still succumb to their disease, underscoring the urgent need for novel therapeutic strategies with potent and durable anti-tumor activity. As in many pediatric cancers, gene expression signatures defining NBL cell state are under epigenetic control. Through epigenetic rewiring of the enhancer landscape, treatment with retinoic acid leads to suppression of oncogenic MYCN expression and subsequently to growth arrest and differentiation. However, the epigenetic and antiproliferative effects of retinoic acid are completely reversible upon drug withdrawal, leading to rapid tumor cell proliferation. Here, we sought to identify epigenetic modifiers that enhance the antiproliferative effects of retinoids in NBL. We conducted a screen with 452 compounds targeting epigenetic modifiers to identify synergistic growth inhibitors. We identified PF-9363, a first-in-class-inhibitor of the histone acetyltransferases KAT6A/B, as synergistically inhibiting NBL growth in combination with retinoic acid in NBL. Importantly, this growth suppression persisted beyond retinoid withdrawal, in stark contrast to retinoid monotherapy. Moreover, the KAT6A/B inhibitor PF-9363 synergizes with RA through sustained downregulation of MYCN and the transcription factors PHOX2B and GATA3, caused by gene expression silencing through PRC2-dependent deposition of H3K27me3 across their regulatory enhancers, extending the antiproliferative and differentiating effects of retinoic acid. In NSG xenograft models of NBL, PF-9363 alone demonstrated significant anti-tumor activity and tumor volumes were significantly reduced compared to vehicle treated mice. Moreover, combination treatment with retinoic acid and PF-9363 led to the most profound and sustained tumor growth suppression, lasting beyond retinoid withdrawal, an effect not observed with either agent alone, where tumors resumed rapid growth following drug removal. Reflecting the epigenetic reprogramming of these tumor cells, expression of GD2 was significantly upregulated in GD2low NBL cells by treatment with retinoic acid plus PF-9363 both in vitro and in vivo, thereby enhancing the efficacy of dinutuximab and anti-GD2 CAR T cell therapy. In conclusion, as KAT6A/B have recently emerged as druggable epigenetic targets in adult cancers—with early-phase clinical trials demonstrating favorable safety profiles and durable responses—our studies highlight KAT6A and KAT6B as promising novel therapeutic targets to enhance the efficacy of differentiation therapy and GD2 immunotherapy in NBL. Citation Format: Nina Weichert-Leahey, Alla Berezovskaya Berezovskaya, Mark W. Zimmerman, Francesca Alvarez-Calderon, Marlana Winschel, Silvi Salhotra Salhotra, Nathaniel Mabe Mabe, Ulrike Gerdemann, Kimberly Stegmaier, Adam D. Durbin, Derek A. Oldridge, Brian J. Abraham, A. Thomas Look. KAT6A and KAT6B are therapeutic targets to enhance the efficacy of differentiation therapy and GD2 immunotherapy in neuroblastoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₂): Abstract nr A020-PR004.
Weichert‐Leahey et al. (Thu,) studied this question.