Background and Aims

CRC is a devastating disease highly modulated by dietary nutrients. mTORC1 contributes to tumor growth and limits therapy responses. Growth factor signaling is a major mechanism of mTORC1 activation. However, compensatory pathways exist to sustain mTORC1 activity following therapies that target oncogenic growth factor signaling. Amino acids potently activate mTORC1 via amino acid sensing GTPase activity towards Rags complexes (GATOR). The role of amino acid sensing pathways in CRC is unclear.

Methods

Human colon cancer cell lines, preclinical intestinal epithelial specific GATOR1 and GATOR2 knockout mouse subjected to colitis induced or sporadic colon tumor models, siRNA screening targeting regulators of mTORC1, and CRC patient tissues were used to assess the role of amino acid sensing in CRC.

Results

We identified loss-of-function mutations of the GATOR1 complex in CRC and show that altered expression of amino acid sensing pathways predict poor patient outcomes. We show that dysregulated amino acid sensing induced mTORC1 activation drives colon tumorigenesis in multiple mouse models. We found amino acid sensing pathways to be essential in the cellular reprogramming of chemoresistance, and chemotherapeutic resistant colon cancer patients exhibited deregulated amino acid sensing. Limiting amino acids in in vitro and in vivo model (low protein diet) reverted drug resistance revealing a metabolic vulnerability.

Conclusions

Our findings suggest a critical role of amino acid sensing pathways in driving CRC and highlights translational implications of dietary protein intervention in CRC.

https://www.gastrojournal.org/article/S0016-5085(22)01273-2/fulltext