Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model.
Agents targeting insulin-like growth factor-I receptor (IGF-IR), including antibodies and small-molecule inhibitors, are currently in clinical development for the treatment of cancers including sarcoma. However, development of resistance is a common phenomenon resulting in failures of anticancer therapies. In light of this problem, we developed two resistant models from the rhabdomyosarcoma cell line Rh41: Rh41-807R, with acquired resistance to BMS-754807, a small-molecule dual-kinase inhibitor targeting IGF-IR and insulin receptor (IR), and Rh41-MAB391R, with resistance to MAB391, an IGF-IR-blocking antibody. In addition, tumor xenograft models were established from Rh41 and Rh41-807R cell lines. Gene expression and DNA copy number analyses of these models revealed shared as well as unique acquired resistance mechanisms for the two types of IGF-IR inhibitors. Each resistant model used different signaling pathways as a mechanism for proliferation. Platelet-derived growth factor receptor α (PDGFRα) was amplified, overexpressed, and constitutively activated in Rh41-807R cells and tumors. Knockdown of PDGFRα by small interfering RNA in Rh41-807R resensitized the cells to BMS-754807. Synergistic activities were observed when BMS-754807 was combined with PDGFRα inhibitors in the Rh41-807R model in vitro. In contrast, AXL expression was highly elevated in Rh41-MAB391R but downregulated in Rh41-807R. Notably, BMS-754807 was active in Rh41-MAB391R cells and able to overcome resistance to MAB391, but MAB391 was not active in Rh41-807R cells, suggesting potentially broader clinical activity of BMS-754807. This is the first study to define and compare acquired resistance mechanisms for IGF-IR-targeted therapies. It provides insights into the differential acquired resistance mechanisms for IGF-IR/IR small-molecule inhibitor versus anti-IGF-IR antibody.
Huang
Fei
F
Bristol-Myers Squibb Company, Princeton, NJ 08543, USA.
Hurlburt
Warren
W
Greer
Ann
A
Reeves
Karen A
KA
Hillerman
Stephen
S
Chang
Han
H
Fargnoli
Joseph
J
Graf Finckenstein
Friedrich
F
Gottardis
Marco M
MM
Carboni
Joan M
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000819:agonists / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D014162:Transfection; D014227:Triazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C545990:BMS 754807; D011720:Pyrazoles; D014227:Triazines; D017526:Receptor, IGF Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha