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  P1.14 - Poster Session 1 - Mesothelioma (ID 194)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Mesothelioma
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10893

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    P1.14-011 - Changes in expression of cancer drug resistance genes in mesothelioma cells exposed to carboplatin (ID 2610)

    09:30 - 09:30  |  Author(s): L.E. Morrison
    • Abstract

    Background
    Background A proportion of patients with mesothelioma respond to chemotherapy consisting of pemetrexed and platinum, but tumour responsiveness most often becomes blunted after several cycles. To discover the mechanism of loss of sensitivity to chemotherapeutic agents, we compared expression of cancer drug resistance genes between platinum sensitive and resistant mesothelioma cells.

    Methods
    Mesothelioma cells generated from three chemo-naïve patients propagated in cell culture were exposed to increasing concentrations of carboplatin until in vitro resistance of at least one log10 concentration difference in IC50 was achieved in dose response cytotoxicity assays. For each individual, cells resistant to carboplatin at 8µg/ml and at 20µg/ml were generated. Control cells from each line were passaged in parallel in medium only. Cells were in log phase growth and culture medium was free of platinum for at least two weeks prior to extraction of RNA using Qiagen RNAeasy Mini kits. High quality RNA (assessed by denaturing gel electrophoresis) was then DNase treated and reverse transcribed using Qiagen RT² Profiler PCR Array reagents. Gene expression in control and platinum resistant cells was determined from the Cancer Drug Resistance PCR Array of (Catalogue Array PAHS-004Z) according to manufacturer’s instructions.

    Results
    SULT1E1 was overexpressed in one mesothelioma line resistant to carboplatin at 8µg/ml, and in two of three resistant to 20µg/ml carboplatin, in comparison with parallel passaged controls. One of three cell lines resistant to carboplatin at both the 8µg/ml and 20µg/ml level overexpressed ERBB3, and another resistant at 20µg/ml overexpressed PPARγ. Drug resistance genes displayed more aberrant expression in cells resistant to higher concentrations of carboplatin.

    Conclusion
    The increase in expression of these three genes in mesothelioma resistant to carboplatin suggests that they may be useful targets for circumvention of resistance, but their mechanistic role in development of platinum resistance requires demonstration. In particular, since PPARγ ligands (e.g. roglitazone) have been shown to sensitise cancer cells to chemotherapeutic agents, and are proposed as anticancer agents, it is possible that the functional effect of PPARγ upregulation is moderating rather than causal. Supported by Cancer Australia.