Nf1 loss promotes Kras-driven lung adenocarcinoma and results in Psat1-mediated glutamate dependence.

Xiaojing Wang,Chengling Zhao,Wei Li,Yuqing Chen,Zhongqing Qian,Hongtao Wang,Huanbai Xu,Yuanbing Shen,Shengping Min,Hongli Liu,Tao Wang,Nan Wu,Xincheng Liu

doi:10.15252/emmm.201809856

Xiaojing Wang, Chengling Zhao + Show 11 more

Open Access

https://doi.org/10.15252/emmm.201809856

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Abstract

Mutations to KRAS are recurrent in lung adenocarcinomas (LUAD) and are daunting to treat due to the difficulties in KRAS oncoprotein inhibition. A possible resolution to this problem may lie with co‐mutations to other genes that also occur in KRAS‐driven LUAD that may provide alternative therapeutic vulnerabilities. Approximately 3% of KRAS‐mutant LUADs carry functional mutations in NF1 gene encoding neurofibromin‐1, a negative regulator of focal adhesion kinase 1 (FAK1). We evaluated the impact of Nf1 loss on LUAD development using a CRISPR/Cas9 platform in a murine model of Kras‐mutant LUAD. We discovered that Nf1 deactivation is associated with Fak1 hyperactivation and phosphoserine aminotransferase 1 (Psat1) upregulation in mice. Nf1 loss also accelerates murine Kras‐driven LUAD tumorigenesis. Analysis of the transcriptome and metabolome reveals that LUAD cells with mutation to Nf1 are addicted to glutamine metabolism. We also reveal that this metabolic vulnerability can be leveraged as a treatment option by pharmacologically inhibiting glutaminase and/or Psat1. Lastly, the findings advocate that tumor stratification by co‐mutations to KRAS/NF1 highlights the LAUD patient population expected to be susceptible to inhibiting PSAT1.

Highlights

Mutations to Kirsten rat sarcoma viral oncogene homolog gene (KRAS) are recurrent in lung adenocarcinomas (LUAD) and are daunting to treat due to the difficulties in KRAS oncoprotein inhibition
The work suggests that tumor stratification by co-mutations to KRAS/NF1 highlights the LAUD patient population expected to benefit from inhibiting PSAT1
As TP53 mutations show prognostic significance in KRAS-mutant LUAD cases and NF1-mutant LUAD tumors show significantly higher rates of TP53 mutation relative to KRAS-mutant LUAD tumors (Redig et al, 2016), we investigated the cooperative effect of silencing Nf1 and p53 expression on the oncogenicity of constitutively active Kras mutants

Summary

Introduction

Mutations to KRAS are recurrent in lung adenocarcinomas (LUAD) and are daunting to treat due to the difficulties in KRAS oncoprotein inhibition. A possible resolution to this problem may lie with co-mutations to other genes that occur in KRAS-driven LUAD that may provide alternative therapeutic vulnerabilities. 3% of KRAS-mutant LUADs carry functional mutations in NF1 gene encoding neurofibromin-1, a negative regulator of focal adhesion kinase 1 (FAK1). We evaluated the impact of Nf1 loss on LUAD development using a CRISPR/Cas platform in a murine model of Kras-mutant LUAD. Nf1 loss accelerates murine Kras-driven LUAD tumorigenesis. Analysis of the transcriptome and metabolome reveals that LUAD cells with mutation to Nf1 are addicted to glutamine metabolism. We reveal that this metabolic vulnerability can be leveraged as a treatment option by pharmacologically inhibiting glutaminase and/or Psat. The findings advocate that tumor stratification by co-mutations to KRAS/NF1 highlights the LAUD patient population expected to be susceptible to inhibiting PSAT1

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