WCLC 2025 - Posters & ePosters-P2.02.28 Proteasome Inhibitor Causes Proteotoxic Death and Reshapes TME in LKB1-Deficient NSCLC by Blocking Er-Stress Repair Addiction

P2.02.28 Proteasome Inhibitor Causes Proteotoxic Death and Reshapes TME in LKB1-Deficient NSCLC by Blocking Er-Stress Repair Addiction

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This study investigates the vulnerability of LKB1 (STK11)-deficient non-small cell lung cancer (NSCLC), a subtype known for resistance to conventional therapies. As the third most commonly mutated gene in lung adenocarcinoma, STK11 deficiency is linked to unique tumor biology and poor treatment responses. The researchers aimed to identify intrinsic susceptibilities and develop effective treatments.<br /><br />Using transcriptomics and Bayesian regression, they explored the specific unfolded protein response (UPR) and endoplasmic reticulum (ER) stress repair mechanisms upon STK11 loss. They discovered that LKB1-deficient lung cancer cells rely heavily on ER stress repair pathways for survival, creating a therapeutic "addiction." This vulnerability was experimentally validated in vitro via proteasome inhibition, which induced selective proteotoxic death in STK11-deficient cells.<br /><br />In vivo, treatment with a proteasome inhibitor not only induced tumor cell death but also remodeled the tumor microenvironment (TME). Notably, the “cold,” immunosuppressive TME characteristic of LKB1-deficient tumors was transformed into a “hot,” immune-active state, enhancing anti-tumor immunity. This was confirmed through transcriptomic deconvolution and immunohistochemistry.<br /><br />The study highlights proteasome inhibitors as promising targeted agents against LKB1-deficient NSCLC by blocking ER-stress repair addiction. These findings also suggest potential synergy of proteasome inhibitors with conventional treatments to overcome therapy resistance.<br /><br />In summary, LKB1-deficient lung cancers are uniquely dependent on ER stress repair, offering a novel therapeutic vulnerability. Proteasome inhibition selectively kills these cancer cells and reshapes the TME to support immune-mediated tumor control. Future research is directed toward combination strategies integrating proteasome inhibitors with standard treatments to improve outcomes in this challenging lung cancer subset.

Asset Subtitle

Zhong-Yi Dong

Meta Tag

Speaker Zhong-Yi Dong

Topic Tumor Biology – Preclinical Biology

Keywords

LKB1 deficiency

STK11 mutation

non-small cell lung cancer

ER stress repair

unfolded protein response

proteasome inhibitors

tumor microenvironment remodeling

immune activation

proteotoxic death

therapy resistance