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Mini Oral session

37MO - Concurrent mutations in STK11 and KEAP1 promote ferroptosis protection and SCD1 dependence in lung cancer

Date

02 Mar 2021

Session

Mini Oral session

Presenters

Triparna Sen

Citation

Annals of Oncology (2021) 32 (suppl_1): S14-S19. 10.1016/annonc/annonc459

Authors

T. Sen

Author affiliations

  • Medicine, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
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Resources

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Abstract 37MO

Background

STK11 and KEAP1 loss are strongly co-associated (p<0.001) in lung adenocarcinoma (LUAD). Our team has found that in a 468-gene panel, co-occurrence of these two mutations is the strongest driver of poor outcome in LUADs, conferring resistance to both standard chemotherapy and immunotherapy, resulting in an average overall survival of less than 8 months from diagnosis. Little is known about the cooperativity and an in-depth understanding of the biological and functional consequences of STK11 and KEAP1 co-mutation is an urgent clinical need that is essential to identify effective therapeutic targets.

Methods

We sequentially profiled 1,235 patients with metastatic LUAD by next generation sequencing (MSK-IMPACT). We used CRISPR/Cas9 to create stable knockouts of STK11, KEAP1, or both genes, in three LUAD lines. We performed cell proliferation, bulk RNAsequencing. Furthermore, we performed CRISPR/Cas9 screens in isogenic in vitro models using a curated “druggable genome” sgRNA library that targets 1,463 genes.

Results

STK11/KEAP1 co-mutation predicts short overall survival in patients with LUAD. STK11/KEAP1 co-mutation promotes tumor cell proliferation and migration in vitro and significantly enhanced tumor growth in vivo. Bulk RNA sequencing demonstrated that STK11/KEAP1 co-mutant cells have higher expression of genes involved in ferroptosis protection and are resistant to ferroptosis inducing agents. CRISPR/Cas9 screen identified ferroptosis regulator SCD as an essential gene required for proliferation and survival of STK11/KEAP1 co-mutant cells. Genetic and pharmacological inhibition of SCD1 prevented the growth of STK11/KEAP1 co-mutant cells and sensitized these cells to ferroptosis induction. Finally, in vivo inhibition of SCD1 significantly delayed tumor growth in STK11/KEAP1 co-mutant LUAD.

Conclusions

This study describes, for the first time, ferroptosis evasion as a survival mechanism for STK11/KEAP1 mutant tumors. We identify SCD as an essential gene in STK11/KEAP1 co-mutant LUAD. SCD1 inhibition, either alone or in conjunction with agents targeting ferroptosis, represents a promising strategy to improve outcomes in this cohort of patients with limited therapeutic options and poor prognosis.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

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