# The critical role of GRP78/BiP MARylation in ER stress of KRAS-mutant colorectal cancer

## TL;DR

This study explores how a specific protein modification helps KRAS-mutant colorectal cancer cells survive and suggests targeting this process could lead to new treatments.

## Contribution

The study identifies a novel role for MARylated GRP78/BiP in maintaining ER stability in KRAS-mutant CRC cells.

## Key findings

- KRAS mutations increase ART1, ER stress, and MARylated GRP78/BiP levels in CRC cells.
- Inhibiting MARylated GRP78/BiP disrupts ER stress pathways and promotes apoptosis in KRAS-mutant CRC cells.
- KRAS-mutant CRC cells are more sensitive to MARylated GRP78/BiP inhibition due to higher ER stability needs.

## Abstract

Nearly 50% of patients with KRAS-mutant colorectal cancer (CRC) currently lack effective targeted therapy. The accumulation of KRAS-mutant proteins can trigger a sustained high level of endoplasmic reticulum (ER) stress, and the UPR-based long-term protective regulatory pathway inhibits the aggregation of unfolded proteins, thereby maintaining the stability of the ER and enabling the continued survival of KRAS-mutant tumors. However, the critical factors that affect the regulation of ER homeostasis in KRAS-mutant CRC are still unclear. Mono-ADP ribosylation (MARylation) catalyzed by ART1 is the most important modification of GRP78/BiP and stabilizes the internal environment of the ER. In this study, KRAS mutation increased the levels of ART1, ER stress, and MARylated GRP78/BiP in CRC cells. Inhibiting MARylated GRP78/BiP can impede the downstream IRE1α/XBP1/TFAF2/JNK and PERK/eIF2α/ATF4 cascades by affecting the binding and dissociation of GRP78/BiP with receptors to hinder the growth of KRAS-mutant CRC cells and accelerate their apoptosis. We propose that KRAS-mutant CRC cells are more sensitive to intervention with MARylated GRP78/BiP because more modifications are needed to maintain ER stability. We also conducted a preliminary study on the specific site of function. Clarifying this molecular mechanism can provide a experimental basis for identifying effective targets for the intervention of KRAS-mutant CRC.

mono-ADP-ribosylated GRP78/BiP affects the ER stress-related signaling pathway to regulate endoplasmic reticulum homeostasis and plays a vital role in the survival of KRAS mutant colorectal cancer cells.