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KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant NSCLC

ABSTRACT: KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant NSCLC

PROVIDER: PRJEB90458 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR15117500_1.fastq.gz	Fastqsanger.gz
	ERR15117500_2.fastq.gz	Fastqsanger.gz
	ERR15117501_1.fastq.gz	Fastqsanger.gz
	ERR15117501_2.fastq.gz	Fastqsanger.gz
	ERR15117502_1.fastq.gz	Fastqsanger.gz

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AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

Project description:Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB) and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+ PD-1+ CD8 T cells, restoring therapeutic response to PD-1 ICB for KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC patients with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.

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Gene expression profile at single cell level of non-malignant cells in KRAS syngeniec mouse tumor models harboring STK11 and/or KEAP1 co-muation

Project description:STK11/LKB1 and KEAP1 mutations are associated with immunotherapy resistance. We employed KRAS syngeneic mouse cells (K) and generated KEAP1 loss (KK) or STK11/KEAP1 loss (KLK) by CRISPR/KO. Then we injected these tumor cells and collected the tumor for single-cell RNA-seq. Our aim is to analyze the impact of STK11 and/or KEAP1 deficiency on the immune microenvironment.

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Project description:The myeloproliferative neoplasms (MPN) frequently progress to blast phase disease, an aggressive form of acute myeloid leukemia. To identify genes that suppress disease progression, we performed a focused CRISPR/Cas9 screen and discovered that depletion of LKB1/Stk11 led to enhanced in vitro self-renewal of murine MPN cells. Deletion of Stk11 in a mouse MPN model caused rapid lethality with enhanced fibrosis, osteosclerosis, and an accumulation of immature cells in the bone marrow, as well as enhanced engraftment of primary human MPN cells in vivo. LKB1 loss was associated with increased mitochondrial reactive oxygen species and stabilization of HIF1α, and downregulation of LKB1 and increased levels of HIF1α were observed in human blast phase MPN specimens. Of note, we observed strong concordance of pathways that were enriched in murine MPN cells with LKB1 loss with those enriched in blast phase MPN patient specimens, supporting the conclusion that STK11 is a tumor suppressor in the MPNs.

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LKB1/STK11 Inactivation Leads to Expansion of Pro-Metastatic Tumor Sub-Population in Melanoma

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