Characterizing response to lapatinib (GW572016) in non-Her2 amplified tumor-derived cell lines

C142 Oncogenic molecular alterations that comprise the underpinnings of malignant transformation and metastasis may directly influence disease stage, survival or response to specific therapeutic agents. A more complete understanding of patterns of occurrence of these alterations is a key component to the development of targeted therapies. High throughput genome-wide technologies to assay nucleic acids are pivotal in the identification of biomarkers that predict response to therapeutic agents, which is critical to maximize the benefit to the patients and accelerate the development of oncology drugs.
 Lapatinib (GW572016) is a selective dual-kinase inhibitor of both EGFR and HER2 tyrosine kinases. Although Her2 positive patients are currently the target population for treatment with lapatinib , specific non-Her2 amplified cases may represent an undeveloped group that may benefit from treatment. We hypothesize that additional genes may play a role in promoting sensitivity or resistance to this compound. As part of an effort to further characterize markers for response to lapatinib , 289 tumor derived cell lines of mixed histology were assayed for sensitivity using a 3-day proliferation assay as well as for DNA copy number alterations and base line transcriptomics using microarray-based techniques. All 8 Her2 amplified cell lines responded, while only 4.6% (13/281) of the non-Her2 amplified set were sensitive (where sensitivity is defined as having an IC50 lapatinib regardless of Her2 status. This includes the greatly increased expression of several cell cycle related genes, including EGFR, Dystanin and IL-1B in responsive lines.
 Identifying non-Her2 amplified populations that may benefit from lapatinib could be a key as such tumors account for 75-80% of all breast-cancer cases and an even larger proportion of other common cancers. These analysis suggest that comprehensive genome characterizations can rediscover known markers of response, as well as identify predictive biomarkers that could identify additional patients for which lapatinib may be beneficial.