STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis

Abstract

Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition. STAT3 inhibition effectively suppressed the adaptive survival of ALK-rearranged lung cancer cells by enhancing ALK inhibition-induced apoptosis. The combined effects were characterized by treatment-induced STAT3 dependence and transcriptional regulation of anti-apoptotic factor BCL-XL. In xenograft study, the combination of YHO-1701 (STAT3 inhibitor) and alectinib significantly suppressed tumor regrowth after treatment cessation with near tumor remission compared with alectinib alone. Hence, this study provides new insights into combined therapeutic strategies for patients with ALK-rearranged lung cancer.

Adaptive Resistance to Lorlatinib via EGFR Signaling in ALK-rearranged Lung Cancer

“…Bcl-xL is involved in the drug resistance of numerous types of tumors, including NSCLC, breast cancer, and ovarian cancer 33 . Previous studies have shown that DT factors, YAP1 and STAT3, promoted apoptosis of ALK-rearranged NSCLC cells via regulation of Bcl-xL 12,13 . We also showed that while EGFR activation results in escape from apoptosis, erlotinib, in combination with lorlatinib, induced apoptosis via inhibition of the anti-apoptotic factor, Bcl-xL.…”

“…Tsuji et al indicated that ALK-TKIs enhance the expression of anti-apoptotic factors mediated via YAP1 upregulation in ALK-rearranged NSCLC cells 12 . Yanagimura et al indicated that inhibition of the adaptive survival via STAT3 combined with an ALK-TKI may improve the outcomes of ALK-rearranged lung cancer 13 . In addition, our previous reports have demonstrated that the inhibition of the tolerant signal via HER3 and c-Jun N-terminal kinase (JNK)/c-Jun in combination with ALK-TKIs dramatically improved the outcome of patients with ALK-rearranged NSCLC 14,15 .…”

EML4‐ALK biology and drug resistance in non‐small cell lung cancer: a new phase of discoveries

“…On-target resistance Off-target resistance Additional resistance ATP site Gatekeeper mutations [64] KRAS-exon 3 mutation [52] Anti-apoptotic pathways [93] ATP site solvent-front mutations (e.g. : G1202R) [64] MET amplification [64] Histological transformation [94] Second-site mutations [46,95] MEK activation [96] Epigenetics [97] Compound mutations PIK3CA mutations [98] Tumour microenvironment [29] Oncogene amplification [46] IGF-1R activation [56] Oncogene loss [46] KRAS G12C mutation [46] ALK-exon 23 mutation [52] RET fusion [52] MAPK pathway [68] TP53 mutation [44] PI3K-AKT pathway [99] JAK-STAT pathway [60] SRC activation [100] EGFR activation [58] KIT activation [64] HER family activation [58] YAP activation [62,66] ROS1+ NSCLC patients [69].…”

Epigenetic regulation in lung cancer

“…This inhibition can lead to decreased tumor cell viability and slow or stop the growth of cancer cells. Alectinib is a targeted therapy that specifically addresses the underlying genetic abnormalities in ALK‐positive NSCLC and has shown promising results in clinical trials 344 …”

“…Alectinib is a targeted therapy that specifically addresses the underlying genetic abnormalities in ALK-positive NSCLC and has shown promising results in clinical trials. 344 Brigatinib is a reversible dual inhibitor of ALK and EGFR that has been shown to inhibit other kinases, such as ROS1. Brigatinib is indicated for the treatment of patients with ALK-positive NSCLC who are intolerant to crizotinib.…”