overcomes resistance to anti-HER therapies in breast cancer.
Introduction: Resistance to anti-HER2 therapy is a common feature in Her2 positive breast cancer. The green tea polyphenol epigallocatechin 3-gallate (EGCG) is an effective antitumoral therapy through the blockade of FASN. We have developed polyphenolic compounds that inhibit FASN with greater efficacy than EGCG. Here we report the anticancer activity of MG
28, one of the new synthesized FASN inhibitors, alone or in combination with trastuzumab, lapatinib, erlotinib and cetuximab in a HER-amplified breast cancer models.
Experimental design: We analysed the cytotoxic effects of MG
28 alone and in combination with trastuzumab, lapatinib, erlotinib, or cetuximab in HER2+ and EGFR+ human breast cancer cells. Combinations of MG
28 with targeted agents were tested for synergism, additivity and antagonism using the isobologram analysis. We further analysed changes in FASN protein levels, in apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase (PARP)], and in activation of HER2, AKT and MAPK.
Results: Combination index analysis showed synergistic cytotoxic effects of MG
28 combined with trastuzumab, erlotinib or lapatinib (p < 0.001) and antagonic effects with cetuximab (p < 0.05) in HER2 overexpressing cells. MG
28 plus lapatinib was significantly correlated with increased apoptosis and inhibition of phosphorilated HER2 and MAPK. Response to co-exposure of MG
28 plus erlotinib was significantly correlated with increased apoptosis and its ability to inhibit HER2, MAPK and AKT phosphorilation. HER2+ cells showed partial resistance to trastuzumab and combined treatment of trastuzumab with MG
28 reversed significantly this resistance and thus correlated with increasing cleavage of PARP and its ability to inhibit phosphorylation of HER2 and AKT.
Conclusion: FASN inhibition seems to be an effective approach to overcome resistance to anti- HER therapies. Our results provide a new therapeutic strategy for further
in vivo combined treatments using drugs that target HER2, EGFR and FASN.
Friday, December 12, 2008 7:00 AM