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870 CoREST inhibition by TNG260 increases expression of immunomodulatory genes in STK11-mutant cancer and sensitizes to immune checkpoint blockade
  1. Leanne Ahronian,
  2. Minjie Zhang,
  3. Preksha Shahagadkar,
  4. Alborz Bejnood,
  5. Alice W Tsai,
  6. Chengyin Min,
  7. Lauren Flynn,
  8. Nikitha Das,
  9. Andre Mignault,
  10. Yi Yu,
  11. Heather DiBenedetto,
  12. Alan Huang,
  13. Adam S Crystal and
  14. Xinyuan Wu
  1. Tango Therapeutics, Boston, MA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Loss of function mutations in STK11 drive immune evasion and cause resistance to immune checkpoint blockade. TNG260 is a small molecule inhibitor of the CoREST complex that increases the expression of immune-related genes in STK11-deficient cancer cells. TNG260 reverses the immune evasion phenotype caused by STK11 loss and induces tumor regressions in STK11-deficient models in combination with anti-PD1.

Methods We discovered and developed TNG260, a small molecule which selectively inhibits the CoREST complex and spares the other Class I HDAC complexes, NCoR, NuRD, and Sin3 (with 500-fold selectivity). Previous reports have shown that combining an LSD1 inhibitor with anti-PD1 results in improved antitumor responses. Since LSD1 is a member of the CoREST complex, the combination of an LSD1 inhibitor with anti-PD1 was evaluated to determine if an LSD1 inhibitor can replicate the effects of TNG260 in an STK11-deficient mouse model that is typically resistant to anti-PD1 monotherapy. We also profiled an AXL inhibitor, which is currently in development for STK11-mutant cancer as a combination approach with pembrolizumab. To determine the mechanism of the TNG260 immunomodulatory effect on tumors, we performed RNA-sequencing and cytokine profiling of STK11-mutant cancer cell lines after treatment with TNG260.

Results TNG260 with anti-PD1 induced tumor regressions in 75% of animals with STK11-deficient tumors. In contrast, an LSD1 inhibitor in combination with anti-PD1 provided limited tumor growth inhibition compared to anti-PD1 alone in an STK11-deficient syngeneic model. Similarly, the AXL inhibitor, bemcentinib, provided a minor enhancement to the tumor growth inhibition seen with anti-PD1 as a single agent in this model. These data suggest that TNG260 outperforms other anti-PD1-based combination therapies in development for STK11-deficient cancer. TNG260 causes transcriptional changes in STK11-mutant cancer cells such as up-regulation of genes involved in antigen presentation and interferon gamma pathway signaling. These results are consistent with cytokine profiling studies which show that TNG260 causes an increase in T cell activity when tumor cells are co-cultured with PBMCs. These findings support previous experiments which demonstrate that TNG260 is an immunomodulatory compound.

Conclusions TNG260 alters expression of immunomodulatory genes in STK11-deficient cancer cells via inhibition of the CoREST complex. Unlike other small molecules being combined with anti-PD1 for STK11-deficient NSCLC, the combination of TNG260 with anti-PD1 drives tumor regressions in STK11-deficient models that are typically resistant to anti-PD1 monotherapy. TNG260 is under investigation in a Phase 1/2 study as a single agent and in combination with pembrolizumab for patients with STK11-mutated, advanced solid tumors.

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