Combating Resistance To Epidermal Growth Factor Recpetor Inhibitors In Triple Negative Breast Cancer

COMBATING RESISTANCE TO EPIDERMAL GROWTH FACTOR RECEPTORINHIBITORS IN TRIPLE NEGATIVE BREAST CANCERbyJULIE M MADDENAugust 2014Advisor: Dr. Julie L BoernerCo-Advisor: Dr. Raymond R MattinglyMajor: Cancer BiologyDegree: Doctor of PhilosophyTriple negative breast cancer (TNBC) patients suffer from a highly malignant andaggressive cancer that lacks an effective targeted therapeutic. Although many TNBCs,both in vitro and in vivo, have increased expression of epidermal growth factor receptor(EGFR), EGFR targeted inhibitors, such as gefitinib (GEF), have yet to demonstrateefficacy. Using mass spectrometry to identify pathways that remain activated in thepresence of GEF, we found that components of the mTOR signaling pathway remainphosphorylated. While inhibiting mTOR with temsirolimus (TEM) decreased mTORsignaling, EGFR signaling pathways remained activated and the TNBC cell linescontinued to proliferate. However, dual treatment with TEM and GEF synergisticallydecreased cell viability in TNBC cells. Interestingly, abrogation of both EGFR andmTOR signaling did not alter the phosphorylation of key growth signaling moleculesincluding MAPK and AKT. Instead, our data have identified the translational controlpathway, specifically, eIF4B as a potentially key regulatory point in EGFR and mTORinhibitor synergy. Further, we have also identified the transcription factor, STAT3 as