Abstract 2866: Exploring the basis for platinum and ionizing radiation combination with R1507 (an anti-IGF1R monoclonal antibody) in a small cell lung cancer (SCLC) model using integrated functional and genomic approaches on both short- and long-term drug exposure reveals adaptive mechanisms
Authors: Ferte Charles , Commo Frederic , Loriot Yohann , Clemenson Celine , Hamama Saad , Bibault Jean-Emmanuel , Gombos Andrea , Chargari Cyrus , Soria Jean-Charles , Deutsch Eric 
Published: August 2012

Introduction: R1507 has single agent activity and remarkable chemo- and radiosensitizing effect in defined SCLC cell lines in vitro. It exhibits a dramatic antitumoral effect when combined to IR and cisplatin in vivo. The molecular mechanisms underlying these effects remain unknown. Materials and methods: Three SCLC cell lines (H69, H146 and H526) were selected according to their specific mutational profile (H146 and H69 cells are mutated for MAP2K4 and both PIK3CA and C-MET, respectively). The effects of R1507 on IGF1R downstream signaling were explored using western blots. Both genomic (HG-U133 plus 2 microarray, Affymetrix) and classical functional analyses were performed on the following conditions: (A) R1507 alone short-term (ST-R1507) (3 hours) vs. long-term (LT-R1507) (4 weeks) exposure, (B) R1507 combined with cisplatin, (C) and with ionizing radiation (IR). Results: (A) ST-R1507 disrupts IGF1R signaling through Akt and MAPK pathways in a dose dependent manner in selected SCLC cell lines. High IGF-1R basal expression is not correlated with sensitivity to R1507. Only cell lines with IGF1R gene amplification (H526 and H146) exhibit sensitivity to R1507. The addition of either MK-2206 (Akt inhibitor) or PHA665752 (c-Met tyrosine kinase inhibitor) to R1507 does not restore the sensitivity to IGF-1R inhibition in H69 cells. The addition of U0126 (MEK inhibitor) to R1507 does not restore the sensitivity to IGF-1R inhibition in H146 cells. LT- vs. ST-R1507 analyses reveal evidence of adaptive mechanisms susceptible to promote tumor escape to R1507 as single agent: (i) activation of cell-cell adhesion, beta-arrestin and MAPK gene expression pathways, (ii) activation of multiple cell surface receptors and intracellular proteins implicated in proliferation, angiogenesis and survival, (iii) transient reduction of phosphorylated IGF-1R staining intensity, in H526 xenografts in vivo. Regarding combination regimens, we identified: (B) the apoptotic mitochondrial and the NER pathways as majorly sensitizing the effects of LT- R1507 to Cisplatin, and (C) the TGF-beta pathway as the key mediator of the sensitization of LT-R1507 to IR. Conclusion: Combined genomic and functional approaches performed under LT-R1507 exposure unravel the activation of multiple alternative signaling pathways that are expected to promote tumor escape. Our study also provides key biological basis for translating the R1507 combined with Cisplatin and IR in the SCLC clinical setting. To analyze both short- and long-term drug exposure appears critical when evaluating new antitumoral regimens.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2866. doi:1538-7445.AM2012-2866