When HER2 inhibition fails: hindering compensatory mechanisms through combinatorial approaches
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Since its approval, trastuzumab has dramatically changed the natural history of HER2-positive early and metastatic breast cancer. Nevertheless, about 15% of patients relapse regardless treatment with adjuvant trastuzumab, whilst almost all patients with metastatic disease inevitably develop resistance. Several new drugs have been developed to overcome the mechanisms of escape from HER2 inhibition, including the alterations of extracellular domain of HER2, the interaction with other receptors, the activation of second messengers and alternative pathways. Among these, lapatinib has shown activity in p95HER2-positive tumors; pertuzumab performs as a potent blocker of HER2 dimerization, PI3K/Akt/mTOR inhibitors, as well as agents against c-Met- or IGF1R, are now being studied in early clinical phase trials. At the same time, novel therapeutic strategy including the concomitant use of hormone therapy are currently ongoing. Since tumor is a dynamic disease, combinatorial approaches appear a promising strategy and a significant effort is now devoted to define the best sequence to treat HER2-positive breast cancer patients.
KEY WORDS: trastuzumab; resistance; lapatinib; pertuzumab; PI3K pathway; dual targeting.