The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer

Area of Science:

• Oncology
• Cancer Metabolism
• Molecular Biology

Background:

• Colorectal cancer (CRC) frequently features oncogenic KRAS mutations and APC tumor suppressor inactivation.
• Targeting KRAS directly remains challenging, with therapies focusing on downstream pathways showing limited efficacy.
• Mutant KRAS significantly alters cancer cell metabolism, notably increasing glutamine utilization to fuel proliferation.

Purpose of the Study:

• To investigate the role of glutamine metabolism and the SLC7A5 transporter in KRAS-mutant colorectal cancer.
• To explore therapeutic strategies targeting metabolic vulnerabilities in therapy-resistant CRC.

Main Methods:

• Utilized mouse models with concomitant Apc and Kras mutations in intestinal epithelium.
• Assessed the impact of SLC7A5 expression and function on colorectal tumorigenesis and metastasis.
• Investigated the mechanistic link between KRAS activation, SLC7A5, amino acid homeostasis, and protein synthesis.
• Evaluated the efficacy of combined targeting of protein synthesis (mTORC1 inhibition) and SLC7A5 deletion in established Kras-mutant tumors.

Main Results:

• Concomitant Apc and Kras mutations profoundly reprogrammed intestinal epithelial metabolism, increasing glutamine consumption.
• SLC7A5, a glutamine antiporter, was found to be critical for colorectal tumorigenesis in both early- and late-stage metastatic models.
• SLC7A5 maintains intracellular amino acid levels post-KRAS activation by reprogramming transcription and metabolism, supporting increased protein synthesis for proliferation.
• Combined inhibition of mTORC1 and Slc7a5 deletion significantly abrogated the growth of established Kras-mutant tumors.

Conclusions:

• SLC7A5 is essential for KRAS-driven colorectal cancer growth by supporting the metabolic demands of increased protein synthesis.
• Targeting SLC7A5, in conjunction with inhibiting protein synthesis, presents a promising therapeutic strategy for therapy-resistant KRAS-mutant CRC.