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.
Highlights
The human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in * 20% of human breast carcinomas and is associated with a more aggressive phenotype and worse prognosis [1].HER receptors family is composed of four closely related tyrosine kinase (TK) receptors: HER1 (EGFR), HER2, HER3, and HER4
As preclinical models of acquired resistance to anti-HER2 drugs, we developed a panel of resistant HER2+ breast cancer cells (SK) with long-term (12 months) and high drug concentration exposure of trastuzumab (SKTR), lapatinib (SKLR) and lapatinib plus trastuzumab (SKLTR) (S1 Fig), following Nahta R et al methodology [31]
We have developed and characterized stable cell lines derived from the HER2-positive SKBr3 cells that are resistant to either trastuzumab (SKTR), lapatinib (SKLR) or both (SKLTR)
Summary
The human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in * 20% of human breast carcinomas and is associated with a more aggressive phenotype and worse prognosis [1].HER receptors family is composed of four closely related tyrosine kinase (TK) receptors: HER1 (EGFR), HER2, HER3, and HER4. A small-molecule TKI targeting the intracellular tyrosine kinase domain of EGFR and HER2, was found to improve time to progression in HER2 breast cancer patients who had progressed to tratuzumab [7]. The molecular mechanisms leading to trastuzumab and lapatinib resistance has been extensively studied [11] These include for example in vivo conversion of HER2+ to HER2- carcinoma after neoadjuvant trastuzumab [12], predominance of the constitutively active HER2 form (p95HER2) [8], overexpression or hyperactivation of other HER family receptors or its ligands [13], amplification of the PI3K/AKT/mTOR pathway by loss of phosphatase and tensin homolog (PTEN) [14], gain-of-function mutation in PI3KCA (encoding the PI3K catalytic isoform p110α) [15] and AKT mutations or amplifications [16]
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