RESUMO
Inhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A. A subset of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also associated with tumour response to HSP90 inhibition. In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is maintained; however, a switch in MCL1 dependence occurs. This can be exploited by the BH3 peptidomimetic ABT737, through non-BCL-2-dependent synthetic lethality.
Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Linhagem Celular Tumoral , Humanos , Peptidomiméticos , Fator de Transcrição STAT5/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Malignant pleural mesothelioma (MPM) is a highly chemoresistant cancer with a poor prognosis. Hypoxia is a specific property of solid tumours, contributes to low apoptotic potential, and can be selectively targeted by bioreductive drugs. Hypoxia-inducible factor 1alpha (HIF-1alpha) is a subunit of a heterodimeric transcription complex that regulates several genes associated with tumour progression and anti-apoptosis. In this study, we measured for the first time the expression of HIF-1alpha in MPM. Our results show that HIF-1alpha is commonly expressed in MPM but not in normal mesothelium, consistent with the presence of hypoxia. HIF-1alpha does not appear to predict survival; however, this study suggests that bioreductive drugs should be investigated in clinical trials of MPM.
Assuntos
Biomarcadores Tumorais/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Mesotelioma/metabolismo , Neoplasias Pleurais/metabolismo , Apoptose , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Progressão da Doença , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Mesotelioma/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Neoplasias Pleurais/patologia , PrognósticoRESUMO
Malignant pleural mesothelioma continues to be a challenging clinical problem. While traditionally, chemotherapy has been thought to be of only modest benefit to patients with this disease, novel antineoplastic agents and combination regimens incorporating these agents are gradually changing this perception. Early attempts at treatment and palliation with single agents such as doxorubicin met with low response rates and little clinical benefit. However, the recently reported clinical benefits of pemetrexed and raltitrexed in combination with cisplatin are changing the perception about the ability of chemotherapy to affect the natural history of the disease. Other combinations, including cisplatin and gemcitabine, have also shown encouraging response rates and clinical activity. Single-agent therapy with vinorelbine may provide useful palliation with low toxicity. Targeted agents developed through increased understanding of the biology of the disease, used alone or as part of multimodal therapy, may provide major clinical gains in the next few years.