title: IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines.
abstract: Insulin-like growth factor receptor 1 (IGF-1R)-targeting therapies are currently at an important crossroad given the low clinical response rates seen in unselected patients. Predictive biomarkers for patient selection are critical for improving clinical benefit. Coupling in vitro sensitivity testing of BMS-754807, a dual IGF-1R/IR inhibitor, with genomic interrogations in 60 human colorectal cancer cell lines, we identified biomarkers correlated with response to BMS-754807. The results showed that cell lines with BRAF(V600E) or KRAS(G13D) mutation were resistant, whereas cell lines with wild-type of both KRAS and BRAF were particularly sensitive to BMS-754807 if they have either higher RNA expression levels of IR-A or lower levels of IGFBP6. In addition, the cell lines with KRAS mutations, those with either insulin receptor substrate 2 (IRS2) copy number gain (CNG) or higher IGF-1R expression levels, were more sensitive to the drug. Furthermore, cell lines with IRS2 CNG had higher levels of ligand-stimulated activation of IGF-1R and AKT, suggesting that these cell lines with IGF-IR signaling pathways more actively coupled to AKT signaling are more responsive to IGF-1R/IR inhibition. IRS2 siRNA knockdown reduced IRS2 protein expression levels and decreased sensitivity to BMS-754807, providing evidence for the functional involvement of IRS2 in mediating the drug response. The prevalence of IRS2 CNG in colorectal cancer tumors as measured by qPCR-CNV is approximately 35%. In summary, we identified IRS2 CNG, IGF-1R, IR-A, and IGFBP6 RNA expression levels, and KRAS and BRAF mutational status as candidate predictive biomarkers for response to BMS-754807. This work proposed clinical development opportunities for BMS-754807 in colorectal cancer with patient selection to improve clinical benefit.
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey. fei.huang@bms.com han.chang@bms.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey. fei.huang@bms.com han.chang@bms.com.
authors.forename: Han
authors.initials: H
authors.lastname: Chang
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Ann
authors.initials: A
authors.lastname: Greer
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hillerman
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Reeves
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Warren
authors.initials: W
authors.lastname: Hurlburt
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: John
authors.initials: J
authors.lastname: Cogswell
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Dharmesh
authors.initials: D
authors.lastname: Patel
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Zhenhao
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Craig
authors.initials: C
authors.lastname: Fairchild
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Rolf-Peter
authors.initials: RP
authors.lastname: Ryseck
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Friedrich G
authors.initials: FG
authors.lastname: Finckenstein
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jackson
authors.affiliation: Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D004252:DNA Mutational Analysis; D005784:Gene Amplification / Q000187:drug effects; D018628:Gene Dosage; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors; D014227:Triazines / Q000494:pharmacology*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C545990:BMS 754807; D014408:Biomarkers, Tumor; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D018976:Insulin-Like Growth Factor Binding Protein 6; C117307:KRAS protein, human; D008024:Ligands; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D014227:Triazines; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins