br Conclusion br Conflict of interest br Introduction The
Conflict of interest
Introduction The human epithelial receptor 2 (HER2 or erbb2) is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases that act through the EGF signaling cascade [1,2]. Approximately 20% of breast cancers overexpress HER2 and consequently, are referred to as HER2-positive (HER2+) breast cancer [, , , ]. The dysregulation of the HER2/EGFR pathway has been shown to result in uncontrolled growth that can contribute to cancer progression [7,8]. The 3-Chlorotyrosine receptor of the HER2 receptor dimers subsequently activates several downstream pathways, including the PI3K (phosphatidylinositol-3-kinase)/Akt (protein kinase B) pathway and the Ras-Raf (rapidly accelerated fibrosarcoma)-MAPK (mitogen-activated protein kinases) pathway [2,9]. These two pathways further modulate cell proliferation, migration, angiogenesis, invasion, apoptosis and other cellular processes [10,11]. Interestingly, unlike other EGFR members, HER2 does not have a specific ligand binding domain and therefore is constitutively active . As a result, HER2 easily interacts with other activated EGFR receptors, making HER2 the preferred dimerization partner for these receptors and consequently an ideal target for breast cancer therapies [, , ]. Amongst the newest cancer therapies being developed are flexible heteroarotinoids (Flex-Hets), which are derived from retinoids and possess promising anti-cancer activity [, , , ]. Studies have shown that one of the first Flex-Hets developed, SHetA2, inhibits growth of the National Cancer Institute's panel of 60 human tumor cell lines by regulating apoptosis, cell growth, differentiation and angiogenesis [17,, , ]. However, compared to most drugs, SHetA2 has higher lipophilicity (logP = 7.09)  which may limit its bioavailability . Therefore, a 2nd generation of Flex-Hets was designed and synthesized to retain the anti-cancer activity of SHetA2 but with lower lipophilicity .
Materials and methods
Discussion One of the most widely used HER2-targeted therapies is trastuzumab, a monoclonal antibody that binds to and blocks HER2 dimerization, which promotes its degradation via endocytic receptor degradation [27,28]. This in turn induces the accumulation of the cyclin-dependent kinase inhibitor (CKI) p27 to promote cell cycle arrest [, , ]. Although patients with HER2+ breast cancer generally show a positive response to trastuzumab, multiple studies indicate that relapse often occurs after prolonged treatment [9,32]. The development of acquired resistance is often associated with mutations that: (1) prevent trastuzumab binding; (2) upregulate HER2 downstream signaling pathways; (3) enhance signaling through alternate pathways; or (4) fail to trigger immune-mediated mechanisms to destroy tumor cells [, , ]. The development of resistance highlights the need to develop new therapeutic options aimed at improving outcomes of patients with HER2+ breast cancer. SHetA2, one of the original Flex-Hets, exhibited promising growth inhibitory effects across multiple cancer types [17,19,20,22]. Previous studies have demonstrated that SHetA2 can induce G1 cell cycle arrest by promoting proteasomal degradation of cyclin D1 in both ovarian and kidney cancer cells [, , ]. SHetA2 has also been shown to target the mitochondria, altering the expression of Bcl-2, caspase 3, and PARP-1 protein, subsequently leading to mitochondrial swelling and ultimately apoptosis [36,38,39]. A study carried out by Myers et al. found that SHetA2 is likewise capable of inhibiting angiogenesis in cancer cells . Furthermore, numerous studies have reported on the relatively low to no toxicity of SHetA2, even at concentrations far exceeding its effective dose [36,40,41]. However, as the utility of SHetA2 is limited by its high lipophilicity (logP) , 2nd generation SHetA2 analogs were designed and synthesized to achieve a lower logP value by modifying the structure of the thiochromane ring while retaining the nitrophenyl group and the thiourea linker .