Identifying Mechanisms of Resistance to SLC6AB Inhibition in CRC Liver Metastasis

Rockefeller University, New York NY

Investigators

Abstract

Even though ranked as the third diagnosed cancer, colorectal cancer (CRC) is the second cause of cancer death globally. Over 70% of CRC tumors metastasize to the liver, which is a major factor in mortality. This drastically diminishes the five-year survival rate, leaving current standard of the care (surgery and chemotherapy) ineffective, due to resistance. This underlines the urgent need for new therapeutic options. The Tavazoie lab has identified a critical survival mechanism in CRC cells, where in hypoxic conditions, metastatic cells secrete creatine kinase Brain (CKB), which converts creatine to phosphocreatine using extracellular ATP. Phosphocreatine is then transferred into the cells via SLC6A8, providing an essential energy source. Inhibition of SLC6A8 with the small-molecule RGX-202 has shown encouraging results in preclinical models and early clinical trials. However, resistance to RGX-202 poses a significant challenge. Unraveling the mechanisms that CRC cells use to survive in the hypoxic liver environment and resist treatments is central for developing more effective targeted therapies. This study intends to discover the mechanisms of resistance to SLC6A8 inhibition in CRC liver metastasis using a multi-omic approach. We hypothesize that adaptive genetic and metabolic alterations drive resistance to RGX- 202, which can be identified and targeted. One specific aim with three sub aims will address this hypothesis: Aim 1: To identify mechanisms of resistance to SLC6A8 inhibition in CRC liver metastasis. Aim 1a: Conduct in vivo CRISPR-Cas9 screen in RGX-202-01 sensitive and resistant CRC liver metastasis model cells to identify genes that cause resistance to SLC6A8 inhibitor in hypoxic liver microenvironment. Aim 1 b: Define metabolic alterations in RGX-202-resistant CRC tumors and identify metabolic pathways that contribute to CRC liver metastases. Aim 1c: Establish the molecular corelates of CRC resistance to RGX-202 using unbiased genomic approaches. Significance of this research is to delineate the genetic and metabolic mechanisms by which CRC cells survive in the hypoxic liver environment and become resistant to SLC6A8 inhibition. This study is innovative as it incorporates in vivo CRISPR screens, metabolomics, and transcriptomics to identify resistance mechanisms and establishes new paradigms for treating therapy-resistant CRC.