TY - JOUR T1 - PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer JF - bioRxiv DO - 10.1101/2021.03.18.435801 SP - 2021.03.18.435801 AU - Sarang S. Talwelkar AU - Mikko I. Mäyränpää AU - Julia Schüler AU - Nora Linnavirta AU - Annabrita Hemmes AU - Simone Adinolfi AU - Matti Kankainen AU - Wolfgang Sommergruber AU - Anna-Liisa Levonen AU - Jari Räsänen AU - Aija Knuuttila AU - Emmy W. Verschuren AU - Krister Wennerberg Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/03/18/2021.03.18.435801.abstract N2 - For non-small cell lung cancer (NSCLC) patients with ALK-rearranged tumors, treatment with ALK inhibitors can improve outcomes. However, clinical resistance typically develops over time, and in the majority of cases resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of an ALK-rearranged clinical tumor specimen, and deployed functional drug screens to identify modulators of resistance to ALK inhibitors. This identified a role for PI3Kβ and EGFR in regulating resistance to ALK inhibition. Furthermore, inhibition of ALK elicited activation of EGFR, and inhibition of PI3Kβ rescued EGFR-mediated ALK inhibitor resistance. In ALK-rearranged primary cultures, cell lines and in vivo xenograft models, combined inhibition of ALK and PI3Kβ prevented compensatory MAPK and PI3K-AKT pathway reactivation and selectively targeted the cancer cells. The combinatorial effect was seen even in the background of TP53 mutations and in epithelial-mesenchymal transformed cells. In conclusion, combinatorial ALK and PI3Kβ inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.Competing Interest StatementThe authors have declared no competing interest. ER -