Lung cancer is the leading cause of cancer mortality worldwide and KRAS is the most commonly mutated gene in lung adenocarcinoma (LUAD). The 78-kDa glucose-regulated protein GRP78/BiP is a key endoplasmic reticulum chaperone protein and a major pro-survival effector of the unfolded protein response (UPR). Analysis of the Cancer Genome Atlas database and immunostain of patient tissues revealed that compared to normal lung, GRP78 expression is generally elevated in human lung cancers, including tumors bearing the KRASG12D mutation. To test the requirement of GRP78 in human lung oncogenesis, we generated mouse models containing floxed Grp78 and Kras Lox-Stop-Lox G12D (KrasLSL-G12D) alleles. Simultaneous activation of the KrasG12D allele and knockout of the Grp78 alleles were achieved in the whole lung or selectively in lung alveolar epithelial type 2 cells known to be precursors for adenomas that progress to LUAD. Here we report that GRP78 haploinsufficiency is sufficient to suppress KrasG12D-mediated lung tumor progression and prolong survival. Furthermore, GRP78 knockdown in human lung cancer cell line A427 (KrasG12D/+) leads to activation of UPR and apoptotic markers and loss of cell viability. Our studies provide evidence that targeting GRP78 represents a novel therapeutic approach to suppress mutant KRAS-mediated lung tumorigenesis.
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We thank Hal Chapman for the SPC-Cre mice, Peter Conti and Jennifer Choi for assistance with PET/CT, and Jorge Nieva and Robert Hsu for tumor samples. The work was supported by NIH grants R01 CA027607 and the Judy and Larry Freeman Chair (ASL), NIH Diversity Supplements (DFR), the Hastings Foundation (BZ, ZB), and NIH grant R35 HL135747 and Ralph Edgington Chair (ZB). We thank the USC Norris Comprehensive Cancer Translational Pathology Core and the USC Molecular Imaging Center (supported by P30 CA014089, 1S10OD012371 and 1S10OD18500) for technical assistance.
Conflict of interest
The authors declare no competing interests.
All protocols for animal use and euthanasia were reviewed and approved by the University of Southern California Institutional Animal Care and Use Committee. Patient lung tissues were obtained in accordance with a protocol approved by the Institutional Review Board of the University of Southern California. Confirmed consent was obtained from all participants.
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Rangel, D.F., Dubeau, L., Park, R. et al. Endoplasmic reticulum chaperone GRP78/BiP is critical for mutant Kras-driven lung tumorigenesis. Oncogene 40, 3624–3632 (2021). https://doi.org/10.1038/s41388-021-01791-9