Open AccessEstablishment of phosphatidylinositol 3‐kinase inhibitor‐resistant cancer cell lines and therapeutic strategies for overcoming the resistance
Author(s) -
Isoyama Sho,
Dan Shingo,
Nishimura Yumiko,
Nakamura Naoki,
Kajiwara Gensei,
Seki Mariko,
Irimura Tatsuro,
Yamori Takao
Publication year - 2012
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12004
Subject(s) - insulin like growth factor 1 receptor , tyrosine kinase , cancer research , gefitinib , cancer , nilotinib , kinase , biology , cancer cell , medicine , epidermal growth factor receptor , signal transduction , receptor , microbiology and biotechnology , growth factor
Acquired resistance is a major obstacle for conventional cancer chemotherapy, and also for some of the targeted therapies approved to date. Long‐term treatment using protein tyrosine kinase inhibitors ( TKI s), such as gefitinib and imatinib, gives rise to resistant cancer cells carrying a drug‐resistant gatekeeper mutation in the kinase domain of the respective target genes, EGFR and BCR – ABL . As for the phosphatidylinositol 3‐kinase inhibitors ( PI 3 K is), little is known about their acquired resistance, although some are undergoing clinical trials. To address this issue, we exposed 11 human cancer cell lines to ZSTK 474, a PI 3 K i we developed previously, for a period of more than 1 year in vitro . Consequently, we established ZSTK 474‐resistant cells from four of the 11 cancer cell lines tested. The acquired resistance was not only to ZSTK 474 but also to other PI 3 K is. None of the PI 3 K i‐resistant cells, however, contained any mutation in the kinase domain of the PIK3CA gene. Instead, we found that insulin‐like growth factor 1 receptor ( IGF 1 R ) was overexpressed in all four resistant cells. Interestingly, targeted knockdown of IGF 1 R expression using specific si RNA s or inhibition of IGF 1 R using IGF 1 R ‐ TKI s reversed the acquired PI 3 K i resistance. These results suggest that long‐term treatment with PI 3 K is may cause acquired resistance, and targeting IGF 1 R is a promising strategy to overcome the resistance.