Target 3 Program

The remarkable clinical activity of immuno-oncology therapies, specifically checkpoint inhibitors, comes from activating certain immune cells to kill cancer cells. However, loss-of-function mutations in STK11 and some other tumor suppressor genes are strongly associated with immune checkpoint inhibitor resistance. TNG260, our Target 3 inhibitor, in combination with immune checkpoint blockade, is designed to address the unmet medical need of immunotherapy-resistant STK11-mutant cancers.

Opportunity

Our synthetic lethal target discovery approach can be adapted to identify druggable tumor-intrinsic targets that do not kill cancer cells directly, but rather attract immune cells to destroy them. In preclinical studies we have shown that Target 3, an undisclosed synthetic lethal target, reverses the immune evasion effect of STK11 (serine-threonine kinase 11) loss-of-function mutations, which are present in approximately 15% of non-squamous lung and cervical cancers, 10% of carcinoma of unknown primary, 5% of breast cancers and 3% of pancreatic cancers.

TNG260

Our state-of-the-art in vivo CRISPR discovery platform enabled the discovery of STK11 as a tumor suppressor that drives immune evasion when not functional in cancer cells.
We engineered a syngeneic mouse tumor model in which STK11 loss of function drives resistance to immune checkpoint blockade.
Using this mouse model with our novel in vivo target discovery platform, we identified Target 3 – a novel drug target that, when inhibited, reverses immune evasion driven by STK11 loss of function.
Treatment of the STK11mut mouse tumor model with TNG260 in combination with anti-PD1 caused complete regressions in 5/8 animals and deep regressions in the remainder
Immune memory was induced in all five animals with complete responses rendering them resistant to rechallenge with the original tumor

Learn more about our USP1 program.