KRAS is the most commonly mutated oncogene in human cancers with limited therapeutic options, thus there is a critical need to identify novel targets and inhibiting agents. The 78-kDa glucose-regulated protein GRP78, which is upregulated in KRAS cancers, is an essential chaperone and the master regulator of the unfolded protein response (UPR). Following up on our recent discoveries that GRP78 haploinsufficiency suppresses both KRASG12D-driven pancreatic and lung tumorigenesis, we seek to determine the underlying mechanisms. Here, we report that knockdown of GRP78 via siRNA reduced oncogenic KRAS protein level in human lung, colon, and pancreatic cancer cells bearing various KRAS mutations. This effect was at the post-transcriptional level and is independent of proteasomal degradation or autophagy. Moreover, targeting GRP78 via small molecule inhibitors such as HA15 and YUM70 with anti-cancer activities while sparing normal cells significantly suppressed oncogenic KRAS expression in vitro and in vivo, associating with onset of apoptosis and loss of viability in cancer cells bearing various KRAS mutations. Collectively, our studies reveal that GRP78 is a previously unidentified regulator of oncogenic KRAS expression, and, as such, augments the other anti-cancer activities of GRP78 small molecule inhibitors to potentially achieve general, long-term suppression of mutant KRAS-driven tumorigenesis.

GRP78

KRAS

Lung cancer

Colon cancer

Pancreatic cancer

Small molecule inhibitors

Kirsten rat sarcoma viral oncogene

78-kilodalton glucose-regulated protein

Unfolded Protein Response

protein kinase R(PKR)-like endoplasmic reticulum kinase

Pancreatic ductal adenocarcinoma

Eukaryotic translation initiation factor 2A

Eukaryotic initiation factor-4A

Eukaryotic translation initiation factor 5A

Eukaryotic translation initiation factor 4E

Eukaryotic translation initiation factor 4E-binding protein 1

© 2022 The Authors. Published by Elsevier Inc.