Dual fatty acid synthase and HER2 signaling blockade shows marked antitumor activity against breast cancer models resistant to anti-HER2 drugs.

Abstract

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 of FASN and HER2 pathways is effective in cells and in breast cancer models refractory to anti-HER2 therapies.

• Authors: Adriana Blancafort, Ariadna Giró-Perafita, Glòria Oliveras, Sònia Palomeras, Carlos Turrado, Òscar Campuzano, Dolors Carrión-Salip, Anna Massaguer, Ramon Brugada, Marta Palafox, Jorge Gómez-Miragaya, Eva González-Suárez, Teresa Puig
• Journal: PloS one (PLoS One) Vol. 10 Issue 6 Pg. e0131241 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26107737 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1,3-bis((3,4,5-trihydroxybenzoyl)oxy)naphthalene
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Naphthalenes
• Quinazolines
• Lapatinib
• temsirolimus
• Gallic Acid
• Catechin
• epigallocatechin gallate
• FASN protein, human
• Fatty Acid Synthase, Type I
• ERBB2 protein, human
• Erbb2 protein, mouse
• Receptor, ErbB-2
• pertuzumab
• Trastuzumab
• Sirolimus

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy)
• Catechin (analogs & derivatives, pharmacology)
• Cell Adhesion
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Fatty Acid Synthase, Type I (antagonists & inhibitors)
• Female
• Gallic Acid (analogs & derivatives, pharmacology)
• Humans
• Lapatinib
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation
• Naphthalenes (pharmacology)
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Sirolimus (analogs & derivatives, pharmacology)
• Trastuzumab (pharmacology)