Metastatic signature in lung cancer is associated with sensitivity to anti-integrin α(V) monoclonal antibody intetumumab.
Intetumumab is a fully human monoclonal antibody that inhibits αv integrins. It has been shown in in vitro assays to effectively inhibit cell viability, metastasis, and adhesion of human cancer cells and endothelial cells. However, the response to Intetumumab varies in different tumor cell lines. To understand the growth inhibition mechanism of Intetumumab and to identify a molecular signature that can predict sensitivity, we focused on lung cancer cell lines and performed a series of proliferation assays. We then assessed the global gene expression profiles, DNA copy number variations, and microRNA profiles from a total of 23 lung cancer lines. The results revealed that lung cancer sensitivity to Intetumumab is associated with several chromosomal alterations, particularly genetic loss at chromosome arm 19p, which resulted in gene expression changes. We identified a genetic signature that can be used to predict Intetumumab sensitivity for lung cancer cell lines. Independently, microRNA analysis revealed a panel of signature microRNAs that includes several markers of epithelial to mesenchymal transition and tumor metastasis such as miR-200 family and miR-205. Both the genetic and microRNA signatures provide insights into the potential mechanism of Intetumumab activity and serve as the first step to develop a patient stratification strategy for Intetumumab therapy in lung cancer.
Janssen Research and Development, Janssen Pharmaceutical Companies of Johnson and Johnson, Spring House, PA, 19477 USA.
Huiqing
H
Liu
Jaehong
J
Park
Carol
C
Manning
Hinrich W H
HW
Goehlmann
Deborah J
DJ
Marshall
D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D056915:DNA Copy Number Variations; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D009362:Neoplasm Metastasis
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D039564:Integrin alphaV; D035683:MicroRNAs; C486839:intetumumab