title: Establishment of phosphatidylinositol 3-kinase inhibitor-resistant cancer cell lines and therapeutic strategies for overcoming the resistance.
abstract: 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 (TKIs), 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 (PI3Kis), 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 ZSTK474, a PI3Ki we developed previously, for a period of more than 1 year in vitro. Consequently, we established ZSTK474-resistant cells from four of the 11 cancer cell lines tested. The acquired resistance was not only to ZSTK474 but also to other PI3Kis. None of the PI3Ki-resistant cells, however, contained any mutation in the kinase domain of the PIK3CA gene. Instead, we found that insulin-like growth factor 1 receptor (IGF1R) was overexpressed in all four resistant cells. Interestingly, targeted knockdown of IGF1R expression using specific siRNAs or inhibition of IGF1R using IGF1R-TKIs reversed the acquired PI3Ki resistance. These results suggest that long-term treatment with PI3Kis may cause acquired resistance, and targeting IGF1R is a promising strategy to overcome the resistance.
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan; Research Laboratory, Zenyaku Kogyo, Tokyo, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Isoyama
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakamura
authors.forename: Gensei
authors.initials: G
authors.lastname: Kajiwara
authors.forename: Mariko
authors.initials: M
authors.lastname: Seki
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Irimura
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009154:Mutation / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D017451:Receptors, Somatomedin / Q000235:genetics; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017451:Receptors, Somatomedin; D014227:Triazines; C510150:ZSTK474; C484760:PIK3CA protein, human