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

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.

Keywords

• ALK‐rearranged lung cancer
• combination treatment
• drug resistance
• EGFR
• EML4‐ALK
• NSCLC