PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer

Wennerberg, K.; Verschuren, E. W.; Talwelkar, S.; Mäyränpää, M. I.; Schüler, J.; Linnavirta, N.; Hemmes, A.; Adinolfi, S.; Kankainen, M.; Sommergruber, W.; Levonen, A.-L.; Räsänen, J.; Knuuttila, A.

doi:10.1101/2021.03.18.435801

bioRxiv · 10.1101/2021.03.18.435801

PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer

Wennerberg, K.·Verschuren, E. W.·Talwelkar, S.·Mäyränpää, M. I.·Schüler, J.·Linnavirta, N.·Hemmes, A.·Adinolfi, S.·Kankainen, M.·Sommergruber, W.·Levonen, A.-L.·Räsänen, J.·Knuuttila, A.

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Abstract

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 PI3K{beta} and EGFR in regulating resistance to ALK inhibition. Furthermore, inhibition of ALK elicited activation of EGFR, and inhibition of PI3K{beta} rescued EGFR-mediated ALK inhibitor resistance. In ALK-rearranged primary cultures, cell lines and in vivo xenograft models, combined inhibition of ALK and PI3K{beta} 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 PI3K{beta} inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.

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Wennerberg, K., Verschuren, E. W., Talwelkar, S., Mäyränpää, M. I., Schüler, J., Linnavirta, N., Hemmes, A., Adinolfi, S., Kankainen, M., Sommergruber, W., Levonen, A.-L., Räsänen, J., Knuuttila, A.. 2021-03-18. PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer. https://doi.org/10.1101/2021.03.18.435801

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