Journal Article

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

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

2023

Overview

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. PI3Kβ inhibitors enhance the response to ALK inhibitors in primary ALK‐rearranged lung cancer cells. PI3Kβ inhibition blocks ALK‐inhibition‐induced cytoprotective reactivation of EGFR signaling, enhancing the cytotoxic effect on both epithelial‐ and mesenchymal‐phenotype cancer cells without affecting normal lung epithelial cells. Combined inhibition of both ALK and PI3Kβ therefore represents a promising approach to improve clinical responses in ALK‐rearranged lung cancers.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / ALK‐rearranged lung cancer / Anaplastic Lymphoma Kinase - genetics / Cancer therapies / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Cells / combination treatment / Drug dosages / drug resistance / Drug screening / Drug therapy / EGFR / EML4‐ALK / Epidermal growth factor / Epidermal growth factor receptors / ErbB Receptors - genetics / Humans / Insulin-like growth factors / Kinases / Lung cancer / Lung cancer, Non-small cell / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / MAP kinase / Mutation / Non-Hodgkin's lymphomas / Non-small cell lung carcinoma / NSCLC / p53 Protein / patient‐derived cells / Phosphatase / Phosphatidylinositol 3-Kinases / PI3Kβ / Protein Kinase Inhibitors - adverse effects / Protein-tyrosine kinase / Proteins / Receptor Protein-Tyrosine Kinases - metabolism / Small cell lung carcinoma / Transformed cells / Tumor proteins / Tumors