The amino acid transporter SLC7A5 drives progression of PI3K-mutant intestinal cancer models and enhances response to MAPK-targeted therapy

Abstract Colorectal cancer (CRC) is a complex disease with key oncogenic pathways, including Wnt, MAPK, and PI3K, co-operating to drive tumour initiation and progression. Loss-of-function mutations in the Wnt-pathway inhibitor APC are the most prominent genetic alterations and are commonly seen as the tumour-initiating event. Here, we have used genetically engineered mouse models to introduce pathway-activating mutations of PI3K (Pik3ca, Pten) and MAPK (Kras) signalling to the mouse gut. Comprehensive characterization of these models reveals pathway-dependent cooperation, leading to marked allele dose-dependent acceleration of tumour formation, underpinned by MYC-driven transcriptional reprogramming and alterations in downstream signalling pathways. We find the amino acid transporter SLC7A5 to be highly upregulated upon activation of PI3K signalling. In human CRCs, SLC7A5expression correlates with the newly defined PDS1 pathway-derived subtype and highly proliferative tumours. Genetic depletion of Slc7a5 in the newly developed PI3K-hyperactive models drastically extends survival by delaying tumour formation, even in aggressive Kras/Pik3caco-mutant mice. Finally, Slc7a5 gene deletion sensitizes these models to targeted MAPK inhibition. Taken together, SLC7A5 drives progression of PI3K-mutant CRCs and is an attractive (co-)target for mutation-specific inhibitors.