RT Journal Article
SR Electronic
T1 PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.18.435801
DO 10.1101/2021.03.18.435801
A1 Sarang S. Talwelkar
A1 Mikko I. Mäyränpää
A1 Julia Schüler
A1 Nora Linnavirta
A1 Annabrita Hemmes
A1 Simone Adinolfi
A1 Matti Kankainen
A1 Wolfgang Sommergruber
A1 Anna-Liisa Levonen
A1 Jari Räsänen
A1 Aija Knuuttila
A1 Emmy W. Verschuren
A1 Krister Wennerberg
YR 2021
UL http://biorxiv.org/content/early/2021/03/18/2021.03.18.435801.abstract
AB 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.