Abstract PR3: Preclinical and molecular profiling data suggest LumB breast cancer as a potential indication for co-targeting IGF1R and mTOR with MK-0646 and MK-8669

Abstract

Abstract There has been increasing interest in developing cancer therapies targeting PI3K pathway nodes. However, inhibition of a single node in PI3K pathway such as mTOR by rapamycin analogues results in compensatory activation of survival signaling pathway such as AKT and thereby limiting monotherapy activity. Therefore, in most tumor types, multipathway inhibition, guided by an in-depth understanding of feedback and crosstalk between pathways, may be required for tumor regression. It is well known that that mTOR inhibition upregulates pAKT via the S6K-IRS2 negative feedback loop. Inhibiting both mTOR and IGF1R may therefore ablate such feedback upregulation and lead to clinical response. However, it is unclear which tumor types will respond to the combination in the clinic. Here, we present preclinical and molecular profiling data that supports LumB breast cancer as a potential indication for MK-8669/MK-0646 (mTOR/IGF1 R inhibitor combination). When a panel of over 60 breast cancer cell lines was treated with MK-8669, ER+ cell lines and HER2+ cell lines were clearly more responsive than the triple negative ones. Meanwhile, the status of the MAPK pathway, as captured by a RAS gene expression signature, correlated with resistance to MK-8669 across the panel. Moreover, MK-8669 treatment unregulated multiple key nodes of the IGF1R pathway in the breast cell line panel, especially IRS2, whose upregulation correlated with the response to MK-8669. Furthermore, IGF1R, whose mRNA level correlates with the response to MK-0646 (IGF1 Ri) in multiple internal and external studies, is the highest in a subset of LumB tumors, suggesting a potential dependency on the IGF1R pathway in those tumors. Finally, a comparison between the gene expression profiles of breast cancer cell lines and tumors revealed that the ER+ breast cancer cell lines only represented the LumB, not LumA, subtype of human breast tumors. Taken together, these findings allow us to hypothesize that LumB breast cancer may be enriched in responders to the MK-0646/MK-8669 combination. In 2009, Merck initiated a phase I trial of MK-8669/MK-0646 in which clinical response was observed in LumB breast cancer patients. A phase II clinical trial has been initiated to test the hypothesis retrospectively. This talk is also presented as Poster A52. Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR3.