In vivo modeling of patient genetic heterogeneity identifies new ways to target cholangiocarcinomaIn vivo modeling of patient genetic heterogeneity identifies new ways to target cholangiocarcinomaYounger NT, Wilson ML, Martinez Lyons A, Jarman EJ, Meynert AM, Grimes GR, Gournopanos K, Waddell SH, Tennant PA, Wilson DH, Guest RV, Wigmore SJ, Acosta JC, Kendall TJ, Taylor MS, Sproul D, Mill P, Boulter L.2022-01-23T23:00:00Z<h3>​Abstract</h3><div><br></div><div>Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC. Novel tumor suppressors were uncovered which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. Focusing on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC revealed that tumor growth relies on Wnt and PI3K signaling. Pharmacological co-inhibition of Wnt and PI3K in vivo impeded ICC growth regardless of mutational profile. Therefore, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment independent of tumor genotype, and inhibitors of these pathways should be levied to treat ICC.<br></div><p><a href="">​Cancer Res</a>. 2022 Jan 24;canres.CAN-21-2556-A.2021.<br></p>394