Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma

Sarah A Best,Kate D Sutherland,Sheryl Ding,Yi Xie,Kaiming Li,Boris Reljic,Gavin M Wright,Matthew E Ritchie,James E Vince,Ariena Kersbergen,Ji-Ying Song,Vivek Rathi,Xueyi Dong

doi:10.1038/s41467-019-12164-y

Abstract

The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively target KRAS-mutant lung cancer. Approximately 20% of KRAS-mutant LUAD carry loss-of-function mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keap1-deficient KrasG12D lung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells. Keap1 loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset of KRAS-mutant LUAD cancers.

Highlights

The Kirsten Rat Sarcoma viral oncogene homolog (KRAS) oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature
In Genetically engineered mouse models (GEMMs), we have previously described a synergy between the Keap1/Nrf[2] and PI3K pathways in LUAD17
We show that Keap1-deficient KrasG12D tumors arise from a bronchiolar cell-of-origin, without the concomitant induction of pro-tumorigenic alveolar macrophage expansion observed in tumors originating from alveolar cells

Summary

Introduction

The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. 20% of KRAS-mutant LUAD carry loss-offunction mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. Keap[1] loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth These studies highlight alternative therapeutic approaches to target this unique subset of KRAS-mutant LUAD cancers. In line with the model that genetic alterations can drive a distinct immune response[12], tumorbearing lungs from KrasG12D-mutant mice exhibit an increase in alveolar macrophages. This is thought to be driven by an inflammatory response[13], though the mechanism is not well understood. Treatment with the PPP inhibitor 6aminonicotinamide (6-AN) abrogated the growth of Keap1deficient tumor cells, suggesting a potential therapeutic approach to target this subset of KRAS-mutant LUAD cancers

Methods

Results

Conclusion