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.

Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer

“…We and others have demonstrated that EGCG displays antitumor activity without affecting food intake or weight loss, which are common side effects of other FASN inhibitors (37,38,47). We have previously shown that EGCG produces apoptosis in vitro and in vivo in breast cancer (19,37,38). Here, EGCG showed strong CPI and high apoptosis in vitro and moderate antitumor activity in vivo.…”

“…Same treatments were assessed in monotherapy. Following treatment, cell viability was measured using the standard colorimetric MTT assay as previously described (19). Combinatorial effects were evaluated using the Interaction index (Ix) ¼ P (% CPI drug alone)/% CPI combination.…”

“…In cancer, however, cells overexpress FASN enzyme to synthesize almost all their fatty acids de novo (14,16). We and others have shown that blocking FASN activity has anticancer activity via the apoptotic pathway in vitro and in vivo (17)(18)(19), by disrupting lipid membrane synthesis and modification of protein palmitoylation and deregulating oncogenic signaling pathways (20,21).…”

Maleimide-Functionalized PEI600 Grafted Polyurethane: Synthesis, Nano-Complex Formation with DNA and Thiol-Conjugation of the Complexes for Dual DNA Transfection

“…So far, nearly all research is dealing with administration of one kind DNA or RNA at a time ("mono transfection"). However, in work such as cell reprogramming (e.g., induced pluripotent stem cells) or the need of multi-expression (e.g., double knock down), requirements of sending two different (or more) DNA or RNA ("dual transfection") are in necessity [5][6][7][8][9]. The conventional manipulation is to dispense a mixture of distinct complexes to cells.…”

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

“…Interestingly, there were also preclinical studies showing that trastuzumab-induced reprogramming of the HER axis resulted in the increase of EGFR and HER3 expression after long-term trastuzumab treatment in cell lines, which may correlate with primary resistance to trastuzumab (48). As mentioned above, trastuzumab resistance in HER2 + BC might be caused by excessive EGFR expression (49,50), making EGFR an effective target to evaluate in response to trastuzumab treatment (51).…”