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NPJ Precision Oncology

NPJ Precision Oncology

IF: 6.8
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Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer

Published:17 November 2024 DOI: 10.1038/s41698-024-00757-w
Takaaki Fujimura, Koh Furugaki, Hayato Mizuta, Satoshi Muraoka, Makoto Nishio, Jun Adachi, Ken Uchibori, Eisaku Miyauchi, Hidetoshi Hayashi, Ryohei Katayama, Shigeki Yoshiura

Abstract

Targeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase–positive non-small cell lung cancer (ALK?+?NSCLC) patient–derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth. We confirmed knockdown of both TNKS1/2 in DTP cells recovered the sensitivity to alectinib. Further, our study suggested knockdown of TNKS1/2 increased stability of Axin1/2, which induced β-catenin degradation and decreased its nuclear translocation, thereby suppressing transcription of antiapoptotic and proliferation-related genes (survivin, c-MYC). Targeting both pathways with alectinib+pan-HER inhibitor and alectinib+TNKS1/2 inhibitor suppressed alectinib-induced DTP cells, and the triple combination almost completely prevented the appearance of DTP cells. In conclusion, combination with ALK-TKI, pan-HER and TNKS1/2 inhibitors has the potential to prevent the emergence of DTP in ALK?+?NSCLC.

Substances (10)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Dacomitinib (PF299804) 1110813-31-4 C24H25ClFN5O2 393 suppliers $10.00-$1703.00
Dacomitinib (PF299804) 1110813-31-4 C24H25ClFN5O2 393 suppliers $10.00-$1703.00
Dacomitinib (PF299804) 1110813-31-4 C24H25ClFN5O2 393 suppliers $10.00-$1703.00
Dacomitinib (PF299804) 1110813-31-4 C24H25ClFN5O2 393 suppliers $10.00-$1703.00
Dacomitinib 1110813-31-4 - Inquiry
Dacomitinib 1110813-31-4 - Inquiry
Dacomitinib (PF299804) 1110813-31-4 C24H25ClFN5O2 - Inquiry
Dacomitinib (PF299804) 1110813-31-4 C24H25ClFN5O2 - Inquiry
Dacomitinib (PF299804) 1110813-31-4 - Inquiry
Dacomitinib (PF299804) 1110813-31-4 - Inquiry

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