Radiosensitisation of low HER-2 expressing human breast cancer cell lines

Hamid, Mogammad Baahith (2015-04)

Thesis (MSc)--Stellenbosch University, 2015.

Thesis

ENGLISH ABSTRACT: Breast Cancer remains one of the world’s leading causes of cancer related deaths amongst women. Its treatment has evolved from invasive, highly toxic therapies to treatments that possess a higher specificity and a lower toxicity. Despite improvements in overall survival, many patients do not benefit from these agents because of acquired and/or inherent tumour resistance, which could hinder treatment efficacy. Novel treatment strategies are, therefore, warranted to address these challenges and to significantly improve patient responses. Inhibiting components of the HER-2 signalling pathway can significantly sensitise breast cancer cells to low doses of ionising radiation. The objective of this study was to inhibit key molecular targets of the human epidermal growth factor receptor 2 (HER-2) signalling pathway and expose breast cancer cell lines to doses of radiation, so as to establish potential therapeutic targets that may be amenable to combined modality therapy, and formulate a cocktail of inhibitors to evaluate its radiosensitising capability. This study found that pre-treatment of two breast cancer cell lines (MDA-MB-231 and MCF-7) with a HER-2 inhibitor (TAK-165) had little or no effect on radiosensitivity. However, a radiation enhancement was observed when these cells were pre-treated either with BEZ235, a dual inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target for rapamycin (mTOR), or a cocktail of TAK-165 and BEZ235. These findings suggest that concurrent inhibition of HER-2, PI3K and mTOR during radiotherapy might improve treatment response of breast cancer patients.

AFRIKAANSE OPSOMMING: Borskanker bly steeds een van die leidende oorsake van sterftes aan kanker in vrouens. Behandeling het vanaf ‘n ingrypende, hoogs toksiese terapie verander na ‘n regimen wat hoogs spesifiek met ‘n laer toksisiteit is. Nogtans trek baie pasiënte geen voordeel uit hierdie nuwe benadering nie, omdat inherente en/of verworwe tumorweerstand daarteen suksesvolle uitkomste verhoed. Nuwe behandelingstrategieë is dus nodig om hierdie uitdagings te bekamp en om resultate in pasiënte aansienlik te verbeter. Inhibisie van komponente van die HER-2-seinoordragkaskade kan borskankerselle gevoelig maak vir lae dosisse van geïoniseerde bestraling. Die doelwit van hierdie studie was om sleutelteikens in die HER-2- seinoordragkaskade te inhibeer en om borskankerselle daarna aan bestralings dosisse bloot te stel. Sodoende word potensiële terapeutiese teikens wat vatbaar is vir gekombineerde modaliteitsterapie geïdentifiseer, waarna ‘n kombinasie van inhibitore geformuleer en geëvalueer kan word ten opsigte van hulle kapasiteit om gevoeligheid vir bestraling te verhoog. Die studie bevind dat voorbehandeling met ‘n HER-2-inhibitor (TAK-165) van borskankersellyne (MDA-MB-231 en MCF-7) min of geen invloed gehad het op stralingsensitiwiteit nie. ‘n Stralingsversterking is egter geïdentifiseer toe die selle vooraf behandel is met óf BEZ-235, ‘n tweevoudige inhibitor van fosforinositied 3-kinase (PI3K) en soogdierteiken vir rapamisien (mTOR), óf ‘n mengsel van TAK-165 en BEZ-235. Hierdie bevindinge suggereer dat gelyktydige inhibisie van die HER-2- seinoordragkaskade, PI3K en mTOR gedurende stralingsterapie moontlik die uitkoms in borskankerpasiënte kan verbeter.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/96786
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