Document resource
Background Non-small cell lung cancer (NSCLC) patients with STK11 loss-of-function mutations (which account for ~20% of all cases) respond poorly to immune checkpoint-based therapies compared to STK11 wild-type lung cancers. Additionally, STK11 mutations are typically mutually exclusive with druggable alterations in EGFR or ALK, leaving these patients underserved by recent advancements in targeted therapies. To address this unmet medical need, we developed TNG260; a novel, highly selective CoREST complex inhibitor, that is being investigated in a Ph1/2 clinical study for evaluation of safety and efficacy in combination with pembrolizumab in advanced STK11-mutant cancers (NCT05887492).Methods Informed by in vivo CRISPR screens, we identified CoREST as a target that, when inhibited, reverses the immune evasion caused by loss of STK11. We developed TNG260, a molecule that, in preclinical studies, was shown to potently inhibit the HDAC1 enzyme within the CoREST complex. It spares HDAC enzymes 3-11, and other Class I HDAC complexes, NCoR, NuRD, and Sin3, which contribute to pan-HDAC inhibitor toxicity.Results Inhibition of CoREST by TNG260 led to increased expression of immunomodulatory genes in STK11-deficient cancer cells in vitro and in vivo. Interestingly, TNG260 increased the expression of interferon pathway and inflammation genes to a greater extent in the STK11-deficient setting than in an STK11 wild-type model that is similarly anti-PD-1 resistant. ChIP-sequencing in these models showed a TNG260-induced enrichment of histone acetylation at immune-relevant gene loci in the STK11-deficient setting compared to wild-type.Syngeneic models engineered to have STK11 knockout respond poorly to anti-PD-1, consistent with clinical observations that patients with STK11-mutant tumors respond poorly to immune checkpoint blockade. The addition of TNG260 to anti-PD-1 caused strong anti-tumor responses, including regressions in most animals. As the majority of STK11-mutated cancers are in NSCLC, we sought to verify our findings in murine lung models. The combination of TNG260 and anti-PD-1 led to complete control of tumor growth in KRAS/STK11 co-mutated NSCLC allograft and autochthonous models.Conclusions This study describes TNG260, a CoREST inhibitor which modulates the expression of key immune genes in STK11-null models. Through this mechanism, TNG260 sensitizes immunotherapy-resistant mouse models to anti-PD-1 treatment, illustrating a potential treatment strategy for patients with STK11-mutated tumors. TNG260 in combination with pembrolizumab is currently being evaluated in patients with STK11-mutated, advanced solid tumors (NCT05887492).