Browsing by Subject "HER2-positive breast cancer"

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    Elucidating the mechanisms of T-DM1 resistance in in vitro models of HER2 overexpressing breast cancer
    (2016-09) Saatci, Özge
    Despite the presence of plethora of anti-cancer therapeutics with a variety of different mechanisms of action, it is still not possible to completely eradicate cancer due largely to the occurrence of refractory tumors even years after completion of the treatment. Such “resistant” tumors are formed over time as few cells, which have gained some advantageous genomic alterations eventually populate the entire organ. A lot of in vitro and in vivo studies are currently being done in order to identify the ways by which cancer cells become resistant to given therapy. This would decipher the weaknesses of the resistant tumors and would provide a means to combat drug resistance. T-DM1 is an anti-HER2 therapeutics, being used in refractory HER2-positive breast cancer patients since 2013. It initially generated a huge excitement owing to the highly favorable clinical findings; however, resistance was developed rapidly after 5-6 months following the initial treatment. Currently; very little is known about the mechanisms of acquired resistance against T-DM1, and therefore, identification of novel targets for the treatment of T-DM1 refractory patients would be highly beneficial. In this thesis, I have developed and characterized the acquired T-DM1 resistance phenotypically, and demonstrated abrogation of drug induced mitotic arrest and apoptosis as two novel mechanisms of resistance. I have further analyzed the genomic landscape of resistance in terms of the enrichment of cancer related processes. Cell cycle was found to be the most significantly enriched process among genes deregulated in T-DM1 resistance as identified by next-generation RNA sequencing. Cell cycle was also shown to be activated in TCGA patients expressing high levels of the TDM1 resistance signature and further supported the importance of rewiring cell cycle for the acquisition of T-DM1 resistance in patients as well. I have further identified two important mitotic genes; PLK1 and TACC3 as the common mediators of resistance in different HER2-overexpressing models by a targeted siRNA screen. I have showed that their genomic or pharmacological inhibition confers sensitization to T-DM1 induced growth inhibition, partially through re-induction of apoptotic cell death. I further uncovered a BCL2 dependency in T-DM1 resistant models which was also found to be associated with T-DM1 resistance as inhibition of Bcl2 enhanced T-DM1 induced growth inhibition. Since T-DM1 refractory HER2-positive breast cancer patients are currently not curable, these pre-clinical findings might guide the future clinical test to improve the survival of this patient subgroup via the usage of PLK1 or BCL2 inhibitors in combination with T-DM1.