PI3Kβ inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer
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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 PI3K beta 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 PI3K beta. In ALK-rearranged primary cultures, the combined inhibition of ALK and PI3K beta 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 PI3K beta-inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.
Original language | English |
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Journal | Molecular Oncology |
Volume | 17 |
Issue number | 5 |
Pages (from-to) | 747-764 |
Number of pages | 18 |
ISSN | 1574-7891 |
DOIs | |
Publication status | Published - 2023 |
- ALK-rearranged lung cancer, combination treatment, drug resistance, EGFR, EML4-ALK, NSCLC, patient-derived cells, PI3K beta, CRIZOTINIB, RESISTANCE, P110-BETA, COMBINATION, MUTATION, AZD8186, BREAST, GROWTH, GENE
Research areas
ID: 339129425