Journal
NPJ PRECISION ONCOLOGY
Volume 6, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41698-021-00250-8
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Funding
- Takeda Pharmaceutical Company Limited
- Takeda Science Foundation
- Japan Research Foundation for Clinical Pharmacology [2018A18]
- Joint Research with the Cancer Research Institute of Kanazawa University
- JSPS KAKENHI [20K22820, 19K08608, 19H03524]
- Japan Agency for Medical Research and Development (AMED) [JP20cm0106203h0005]
- Grants-in-Aid for Scientific Research [20K22820, 19H03524, 19K08608] Funding Source: KAKEN
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This study elucidates the pivotal role of HER3 activation in the emergence of drug-tolerant cells in ALK-rearranged lung cancer, and finds that inhibiting HER3 signals combined with ALK-TKI treatment dramatically improves outcomes in ALK-rearranged lung cancer with mesenchymal features.
Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features.
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