# name
Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs

# metadata.dc.description.abstract[].value
Blocking the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of HER2-positive
breast carcinoma cells. The hypothesis is that blocking FASN, in combination with anti-
HER2 signaling agents, would be an effective antitumor strategy in preclinical HER2+
breast cancer models of trastuzumab and lapatinib resistance. We developed and molecularly
characterized in vitro HER2+ models of resistance to trastuzumab (SKTR), lapatinib
(SKLR) and both (SKLTR). The cellular interactions of combining anti-FASN polyphenolic
compounds (EGCG and the synthetic G28UCM) with anti-HER2 signaling drugs (trastuzumab
plus pertuzumab and temsirolimus) were analyzed. Tumor growth inhibition after treatment
with EGCG, pertuzumab, temsirolimus or the combination was evaluated in two in
vivo orthoxenopatients: one derived from a HER2+ patient and another from a patient who
relapsed on trastuzumab and lapatinib-based therapy. SKTR, SKLR and SKLTR showed
hyperactivation of EGFR and p-ERK1/2 and PI3KCA mutations. Dual-resistant cells
(SKLTR) also showed hyperactivation of HER4 and recovered levels of p-AKT compared
with mono-resistant cells. mTOR, p-mTOR and FASN expression remained stable in
SKTR, SKLR and SKLTR. In vitro, anti-FASN compounds plus pertuzumab showed synergistic
interactions in lapatinib- and dual- resistant cells and improved the results of pertuzumab
plus trastuzumab co-treatment. FASN inhibitors combined with temsirolimus displayed
the strongest synergistic interactions in resistant cells. In vivo, both orthoxenopatients
showed strong response to the antitumor activity of the combination of EGCG with pertuzumab
or temsirolimus, without signs of toxicity. We showed that the simultaneous blockade

# metadata.dc.source[].value
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

# metadata.dc.title[].value
Dual Fatty Acid Synthase and HER2 Signaling Blockade Shows Marked Antitumor Activity against Breast Cancer Models Resistant to Anti-HER2 Drugs