LIN28B-mediated activation of the PI3K/AKT pathway promotes metastasis and unravels a new therapeutic vulnerability in colorectal cancer

Colorectal cancer (CRC) remains a leading cause of cancer death, primarily due to metastatic spread. LIN28B, an RNA-binding protein overexpressed in 30% of CRCs, acts as an oncogene and promotes CRC metastasis. However, the mechanisms through which LIN28B drives these effects remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, leading to enhanced activation of the PI3K/AKT pathway and increased metastatic potential in mice. We developed genetically engineered mouse models (GEMMs) with mutant PIK3CA that are the first to exhibit primary intestinal tumors progressing to liver metastases with an intact immune system. Pharmacological inhibition with the PI3Kα-specific inhibitor alpelisib effectively reduced migration and invasion in vitro, as well as metastasis in vivo. Treatment of CRC patient-derived organoids (PDOs) with alpelisib, the AKT inhibitor capivasertib, and/or the S6K inhibitor LY2584702 demonstrated the potential of pathway inhibition to impair tumor growth. Tissue microarrays from CRC patients further indicated that pathway activation correlates with disease progression. These findings underscore the critical role of the PI3K/AKT pathway in CRC metastasis and open new avenues in targeted inhibition and combination therapies in metastatic CRC (mCRC).