RRC ID 63055
Author Wang R, Yamada T, Kita K, Taniguchi H, Arai S, Fukuda K, Terashima M, Ishimura A, Nishiyama A, Tanimoto A, Takeuchi S, Ohtsubo K, Yamashita K, Yamano T, Yoshimura A, Takayama K, Kaira K, Taniguchi Y, Atagi S, Uehara H, Hanayama R, Matsumoto I, Han X, Matsumoto K, Wang W, Suzuki T, Yano S.
Title Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer.
Journal Nat Commun
Abstract Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.
Volume 11(1)
Pages 4607
Published 2020-9-14
DOI 10.1038/s41467-020-18442-4
PII 10.1038/s41467-020-18442-4
PMID 32929081
PMC PMC7490421
MeSH Acrylamides / pharmacology Acrylamides / therapeutic use* Aged, 80 and over Aniline Compounds / pharmacology Aniline Compounds / therapeutic use* Animals Carcinoma, Non-Small-Cell Lung / drug therapy Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Cell Survival / drug effects ErbB Receptors / genetics Gene Expression Regulation, Neoplastic / drug effects Hepatocyte Nuclear Factor 3-alpha / metabolism Humans Imidazoles / pharmacology Lung Neoplasms / drug therapy* Lung Neoplasms / genetics* Lung Neoplasms / pathology Male Mice Models, Biological Mutation / genetics* Phosphorylation / drug effects Proto-Oncogene Proteins / metabolism* Pyrazines / pharmacology RNA, Messenger / genetics RNA, Messenger / metabolism Receptor Protein-Tyrosine Kinases / metabolism* Receptor, IGF Type 1 / antagonists & inhibitors* Receptor, IGF Type 1 / genetics Receptor, IGF Type 1 / metabolism Up-Regulation / drug effects
IF 12.121
Human and Animal Cells PC-9(RCB4455)