Undermining Glutaminolysis Bolsters Chemotherapy While NRF2 Promotes Chemoresistance in KRAS-Driven Pancreatic Cancers

Abstract

Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for patients with pancreatic cancer and contributes to a high rate of recurrence. Oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. Here, we show that NRF2 contributed to chemoresistance and was associated with a poor prognosis in patients with pancreatic cancer. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. In addition, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for patients with pancreatic cancer harboring KRAS mutation.

The Role of Reactive Oxygen Species in Arsenic Toxicity

“…Beyond their function in defencing arsenic toxicity, SGs have been proposed to alter multiple signaling pathways, such as the JNK, Wnt, and mammalian target of rapamycin (mTOR) pathways, by intercepting and sequestering signaling components [178]. Accordingly, SG formation is a marker of chemoresistance and is upregulated by the production of a prostaglandin (15d-PGJ2), which is controlled by NRF2, in mutant v-Ki-ras 2 Kirsten rat sarcoma viral oncogene homolog (KRAS) cells [179]. The two antioxidant systems mentioned above, NRF2 and SGs, may intertwine in response to environmental stress, although the underling mechanism is not fully understood.…”

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies

“…A recent study suggests that methylation on arginine 248 inhibits MDH1 catalytic activity and dimerization by coactivator-associated arginine methyltransferase 1 (CARM1), and KRAS suppresses CARM1-mediated MDH1 methylation, contributing to glutamine metabolism in pancreatic cancer (19). Additionally, oncogenic KRAS-induced NRF2 could upregulate glutaminolysis through increasing the expression of major glutamine metabolism intermediates such as GLS1, GOT1, and Na + -independent cystine/glutamate antiporter SLC7A11 (also known as xCT) (20).…”

Metabolic features of cancer cells in NRF2 addiction status

“…While multiple advantageous aspects of the metabolic reprogramming for NRF2-addicted cancer cells have been described, metabolic liabilities resulting from NRF2-dependent reprogramming have also been investigated. Romero et al conducted a CRISPR/Cas9 genetic screen with KEAP1-mutant lung cancer cells and found that NRF2-addicted cancer cells are highly dependent on glutamine uptake, and that, consequently, inhibition of glutamine-derived glutamate by glutaminase inhibition effectively suppresses NRF2-addicted lung cancers (Romero et al 2017;Mukhopadhyay et al 2020). Satisfying the increased demand for glutamine/ glutamate is likely to be one of the critical requirements for the establishment of NRF2-addiction in cancer cells.…”