Intrinsic Resistance to Cixutumumab Is Conferred by Distinct Isoforms of the Insulin Receptor.
Despite a recent shift away from anti-insulin-like growth factor I receptor (IGF-IR) therapy, this target has been identified as a key player in the resistance mechanisms to various conventional and targeted agents, emphasizing its value as a therapy, provided that it is used in the right patient population. Molecular markers predictive of antitumor activity of IGF-IR inhibitors remain largely unidentified. The aim of this study is to evaluate the impact of insulin receptor (IR) isoforms on the antitumor efficacy of cixutumumab, a humanized mAb against IGF-IR, and to correlate their expression with therapeutic outcome. The data demonstrate that expression of total IR rather than individual IR isoforms inversely correlates with single-agent cixutumumab efficacy in pediatric solid tumor models in vivo. Total IR, IR-A, and IR-B expression adversely affects the outcome of cixutumumab in combination with chemotherapy in patient-derived xenograft models of lung adenocarcinoma. IR-A overexpression in tumor cells confers complete resistance to cixutumumab in vitro and in vivo, whereas IR-B results in a partial resistance. Resistance in IR-B-overexpressing cells is fully reversed by anti-IGF-II antibodies, suggesting that IGF-II is a driver of cixutumumab resistance in this setting. The present study links IR isoforms, IGF-II, and cixutumumab efficacy mechanistically and identifies total IR as a biomarker predictive of intrinsic resistance to anti-IGF-IR antibody.


CONCLUSIONS
This study identifies total IR as a biomarker predictive of primary resistance to IGF-IR antibodies and provides a rationale for new clinical trials enriched for patients whose tumors display low IR expression.
Eli Lilly and Company, New York, New York.
Amelie
A
Forest
Eli Lilly and Company, New York, New York.
Michael
M
Amatulli
Eli Lilly and Company, New York, New York.
Dale L
DL
Ludwig
Eli Lilly and Company, New York, New York.
Christopher B
CB
Damoci
Eli Lilly and Company, New York, New York.
Ying
Y
Wang
Eli Lilly and Company, New York, New York.
Colleen A
CA
Burns
Eli Lilly and Company, Indianapolis, Indiana.
Gregory P
GP
Donoho
Oncotest, Freiburg, Germany.
Nina
N
Zanella
Oncotest, Freiburg, Germany.
Heinz H
HH
Fiebig
Eli Lilly and Company, New York, New York.
Marie C
MC
Prewett
Eli Lilly and Company, New York, New York.
David
D
Surguladze
Eli Lilly and Company, New York, New York.
James T
JT
DeLigio
Nationwide Children's Hospital, Columbus, Ohio.
Peter J
PJ
Houghton
Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
Malcolm A
MA
Smith
Eli Lilly and Company, New York, New York. ruslan.novosiadly@lilly.com.
Ruslan
R
Novosiadly
D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D020033:Protein Isoforms; C557414:cixutumumab; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin