Poster Sessions

C-62

Hark Kim

H. Kim, I. Choi, M. Yi, A. Oshima, C. Kim, E. Kim, T. Lee, J. Ra, R. Stephens, J. Green

Identification of a gene signature predictor for resistance to cancer chemotherapy in patients suggests tumor resistance evolves through clonal selection

Acquired resistance to cancer chemotherapy is the major reason why metastatic cancers cannot be cured by chemotherapy. Despite the clinical significance, mechanisms of resistance in patients have not been elucidated. In order to gain insight into the clinically relevant mechanisms of acquired drug resistance, we obtained sequential biopsy tissue samples from 123 metastatic gastric cancer patients prior and during their course of 5-fluorouracil and cisplatin combination chemotherapy. Biopsy was performed before chemotherapy and at the time of disease progression (progressive disease). Sequential biopsy samples were collected from 22 patients who entered into a partial response and then developed progressive disease during chemotherapy indicating the development of chemo-resistant tumors. All samples were profiled using the Affymetrix U133A microarray. Two major analyses were performed to: 1) identify an initial gene signature predicting whose survival would be prolonged by chemotherapy; and 2) compare initial good and poor prognosis tumor signatures with signatures from tumors that became resistant to chemotherapy. Importantly, genes were shared between these two gene sets [LS and KS p values<10-7], suggesting that these genes may be critical in chemotherapy resistance and are now being functionally tested. Many of these genes are related to the DNA repair. When lower stringency tests are applied to the two types of analyses, the 2 gene sets share many genes in common, significantly more than are expected by chance [LS and KS p values<10-7]. This result suggests that a clonal selection model may significantly contribute to the acquired drug resistance for metastatic gastric cancer patients treated with 5-FU/cisplatin. This is the first genome-wide study addressing clinically relevant mechanisms of acquired resistance to cancer chemotherapy and may be applicable to common solid tumors in which drug response is rarely complete or durable.