Trastuzumab has proven to be a very effective therapy for HER2-positive breast cancer, but de novo oracquired resistance limits its long-term value. New observations from our laboratory suggest severalhypotheses on the mechanisms of resistance to trastuzumab and other therapies targeting the HER network.First, our results suggest that this resistance might stem from incomplete blockade of the signals generatedfrom the various HER-family dimer pairs in the network input layer. Using a limited number of HER2-overexpressing xenograft models we have found that combined drug therapies designed to more completelyblock these heterodimers can overcome resistance to single agents and are even capable of eradicatingmany of these tumors in mice. Our preclinical models and preliminary patient data also suggest alternativemechanisms for resistance to HER-directed therapy that involve the estrogen receptor in some tumors andthe MUC4 mucins in others.Here we propose a series of preclinical studies and an early phase clinical trial to begin to test thesehypotheses. Specifically we will: 1) Confirm our preliminary data that resistance to single-agent HERtargetedtherapy can be overcome by various combinations of trastuzumab, lapatinib, and pertuzumab,designed to more completely block signaling from the HER network input layer, in a large panel of HER2-amplified breast cancer cell lines, and to identify and establish models resistant to these single andcombined antiHER2 drugs for later studies; 2) Determine using these various preclinical HER2-positivemodels whether upregulation of ER or ER signaling to an alternative survival pathway can be induced byHER blockade as a resistance mechanism, and whether simultaneous targeting of ER and HER2 is thennecessary for optimal treatment; 3) Investigate whether upregulation of MUC4 causes resistance to HERtargetedtherapy in our preclinical in vivo model system, thereby providing a new potential diagnostic andtreatment target to investigate in human samples; 4) Lead a multi-institutional phase 2 neoadjuvant clinicaltrial of lapatinib combined with trastuzumab, with serial tissue sampling to assess molecular mechanisms ofaction and resistance, in order to begin to translate our exciting preclinical findings to patients. This work willfacilitate new strategies to circumvent resistance to HER-targeted therapy for improved patient survival.
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