Author of

• 12418

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  P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

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

  • 12427

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    P3.05-009 - Metabolic Reprogramming Overcomes Resistance to ABT-737 -induced Apoptosis in Pre-clinical Models of Malignant Pleural Mesothelioma (ID 1963)

    09:30 - 09:30  |  Author(s): M. Macfarlane
    • Abstract

    Background
    Malignant mesothelioma (MM) is an aggressive, fatal, tumour of the pleura or peritoneum and is strongly related to asbestos exposure. Clinically, there is no curative therapy for MM and the profound chemoresistance of MM is well documented, reportedly being due to the ability of MM cells to escape cell death. Unravelling the molecular mechanisms employed by MM cells to evade cell death will therefore provide new insights into key cell death pathways that may be targeted for successful therapy. Currently, the Bcl-2 repertoire is an undervalued and attractive pharmacological target for mesothelioma therapy. The aims of this study were to investigate the sensitivity of MM to the BH3-mimetic, ABT-737, and identify mechanisms of overcoming resistance to support personalized therapy.

    Methods
    Sensitivity to the highly selective BCL-2/BCL-XL antagonist, ABT-737, was investigated using FACs-based analysis and immunoblotting techniques in a panel of MM cell lines and tumour cells isolated from freshly resected MM tumours. In addition, patient-derived tumour explants were similarly analysed, providing a clinically relevant 3D mesothelioma model. Furthermore, to explore the possibility that tumour cell metabolism may modulate the sensitivity of MM cells to ABT-737, we investigated the effect of inhibiting glycolysis with 2-deoxyglucose (2-DG) on ABT-737 -induced apoptosis in relevant pre-clinical models of MM.

    Results
    The majority of MM cell lines and freshly-derived cultured tumour cells were resistant to ABT-737, suggesting a deregulation of cell death signalling at the level of mitochondria. Aerobic glycolysis (Warburg effect) is a process by which tumour cells gain not only growth advantage (providing much needed “building blocks”) but also an increased survival potential. Importantly we report that, in MM, glycolysis can be inhibited by 2-deoxyglucose(2-DG), a competitive inhibitor of hexokinase. Although exposure to 2-DG did not induce cell death, 2-DG induced a time- and concentration-dependent potentiation of ABT-737 -induced apoptosis in either established mesothelioma cell lines or newly-derived tumour cells from patients. BCL-2-family member profiling revealed that, while the predominant pro-survival members expressed in MM were MCL-1 and BCL-XL, 2-DG selectively decreased MCL-1 protein levels, a leading cause of resistance to ABT-737 in other tumour models.

    Conclusion
    High constitutive levels of MCL-1 most likely explain the inherent resistance of MM cells to the highly selective BCL-2/BCL-XL antagonist, ABT-737. Importantly, 2-DG-dependent down-regulation of MCL-1 provides a potential mechanism for overcoming resistance to ABT-737 in the clinical setting.