trastuzumab Powerpoint Presentation

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trastuzumab

by: drraj12319

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Slide 1 :

Preclinical rationale for Herceptin treatment beyond progression in HER2-positive breast cancer

Slide 2 :

Established chemotherapy resistance mechanisms Impaired drug uptake Active drug efflux, eg by ABC transporters (P-glycoprotein, MDR2, BCRP, MRP1-6 etc) Enhanced drug metabolism, eg by P450 enzymes Alterations of intracellular target, eg tubulin Upregulation of DNA repair in tumour cells Upregulation of signalling pathways, eg anti-apoptotic genes (bcl-2, XIAP etc)

Slide 3 :

Hypothetical mechanisms of resistance to Herceptin (1) Selection of HER2-negative cells in a heterogeneous tumour Outgrowth of HER2-negative tumours from an originally mixed tumour cell population Defective interaction of Herceptin with HER2 Masking of Herceptin-binding epitope of HER2 Alterations in Herceptin-binding epitope of HER2 Loss of HER2 ECD by shedding or alternative initiation of translation on HER2 gene Kunitomo et al 2004; Nagy et al 2005; Tanner et al 2004; Stephens et al 2004; Stephens et al 2005; Anido et al 2006 HER2, human epidermal growth factor receptor 2; ECD, extracellular domain

Slide 4 :

Hypothetical mechanisms of resistance to Herceptin (2) Changes in downstream signalling proteins which eventually disconnect growth regulation from HER2 PIK3CA mutations resulting in constitutively active PI3-kinase Loss of PTEN function leading to persistent signalling activity via the PI3K/Akt survival pathway Changes in cyclin-dependent kinase inhibitor p27kip1 Berns et al 2007; Nagata et al 2004; Crowder et al 2004; Pandolfi 2004; Kute et al 2004; Nahta et al 2004

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