A1 Refereed original research article in a scientific journal

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




AuthorsTalwelkar Sarang S, Mäyränpää Mikko I, Schüler Julia, Linnavirta Nora, Hemmes Annabrita, Adinolfi Simone, Kankainen Matti, Sommergruber Wolfgang, Levonen Anna-Liisa, Räsänen Jari, Knuuttila Aija, Verschuren Emmy W, Wennerberg Krister

PublisherElsevier

Publication year2023

JournalMolecular Oncology

Journal name in sourceMolecular oncology

Journal acronymMol Oncol

ISSN1574-7891

eISSN1878-0261

DOIhttps://doi.org/10.1002/1878-0261.13342(external)

Web address https://www.doi.org/10.1002/1878-0261.13342(external)

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/178580300(external)


Abstract

Treatment with anaplastic lymphoma kinase (ALK) inhibitors significantly improves outcome for non-small-cell lung cancer (NSCLC) patients with ALK-rearranged tumors. 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 ALK-inhibitor response. This identified a role for PI3Kβ and EGFR inhibition in sensitizing the response regulating resistance to ALK inhibition. Inhibition of ALK elicited activation of EGFR, and subsequent MAPK and PI3K-AKT pathway reactivation. Sensitivity to ALK targeting was enhanced by inhibition or knockdown of PI3Kβ. In ALK-rearranged primary cultures, the combined inhibition of ALK and PI3Kβ prevented the EGFR-mediated ALK-inhibitor resistance, and selectively targeted the cancer cells. The combinatorial effect was seen also in the background of TP53 mutations and in epithelial-to-mesenchymal transformed cells. In conclusion, combinatorial ALK- and PI3Kβ-inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.


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Last updated on 2024-26-11 at 21:51