Scope of this dissertation Sample Clauses

Scope of this dissertation. This dissertation aims to use the knowledge by which resistance to lapatinib is acquired to develop novel therapeutic treatments for patients with HER2-overexpressing breast cancer. The PI3K/Akt/mTOR and MEK/ERK pathways have been linked to the development of resistance to HER2 targeted therapies. I propose that combination lapatinib treatment and inhibition of the either the PI3K/Akt/mTOR pathway or combination lapatinib treatment and inhibition of the MEK/ERK pathway will achieve an optimal lapatinib response. The data reveals that reduced lapatinib sensitivity is associated with an inability of lapatinib to inhibit both Akt and MEK/ERK phosphorylation. An investigation of the role of Akt in lapatinib resistance demonstrated that the transfection of constitutively active Akt reduces lapatinib sensitivity, while kinase-dead Akt increases sensitivity. Knockdown of 4EBP1 also increases lapatinib sensitivity, in contrast to p70S6K knockdown, which does not affect response to lapatinib. Further, the pharmacologic inhibition of mTOR using rapamycin or ridaforolimus increases lapatinib sensitivity and reduces Akt phosphorylation levels in cells that show poor response to single agent lapatinib, including those transfected with hyperactive Akt. An evaluation of the role that MEK/ERK plays in lapatinib resistance demonstrates that genetically and pharmacologically blocking MEK/ERK signaling improves response to lapatinib. Also, combination MEK inhibitor plus lapatinib results in a reduced nuclear expression of the MEK/ERK downstream proto-oncogene FOXM1. In addition, xenograft studies demonstrate that pharmacologic inhibition of MEK increases lapatinib sensitivity in HER2-overexpressing breast cancers that are resistant to trastuzumab and lapatinib. This dissertation provides mechanisms by which resistance to lapatinib is achieved, and strongly supports future clinical trials of combination lapatinib plus mTOR inhibition, as well as combination lapatinib plus MEK inhibition.
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