Potential treatments targeting cell-intrinsic pathways mediating cancer cell plasticity
One of the most targeted proteins in the MAPK pathway is the MEK protein. MEK targeting
drugs have been observed to lead to improvement in the prognosis of breast cancer patients.
One such targeted therapy involved a combinational therapy of RAF/MEK inhibitor
CH5126766 alongside Eribulin in TNBC and it was observed that this
combinational mechanism was successful in inhibiting apoptosis and cell migration, thus
contributing to tumor growth68. In another study, dual inhibition of MEK1/2 and MEK 5 by
using inhibitors Cobimetinib and Trametinib resulted in the suppression of EMT in triple
negative breast cancer69. Mohan et al have also shown that Brucein D (BD) which is an
inhibitor targeting the p38 pathway lead to apoptosis and decrease viability of the breast cancer
cells induced by the MAPK pathway70. Alongside MEK inhibitors, the use of RNA binding
proteins has also been elucidated. In one study, RNA binding protein QKI was observed to
suppress the breast cancer cell progression by directly binding to RASA 1 and activating the
MAPK signaling pathway71
PI3K/AKT/mTOR pathway accounts as an altered pathway in breast cancer cell plasticity. Inhibition of the pathway using different small molecule inhibitors targeting different components of the pathway has emerged as one of the prime research interests among researchers. Various different small inhibitors that target the PI3K pathway are being looked into as potential treatment alternatives. In vitrostudies on inhibitors like Buparlisib, Pictilisib, Alpelisib, Taselisib have led to the pro-apoptotic and anti-proliferative activity on breast cancer cell lines72. Natural compounds have also started to gain popularity for potential targeting of the pathway. One such bibenzyl compound is Gigantol extracted from orchids belonging to the Dendrobium genus. It has been observed to downregulate pathway in cancer cells thus in turn inhibiting proliferation and induce apoptosis. The study involved in silico determination of the potential pathway by which Gigantol acts followed by in vitro assays to elucidate effect of the same on breast cancer cell line73. Another natural compound that has emerged as a potential candidate for therapy in TNBC is a novel Anilide Shikonin ester- M9. Ma et al. elucidated effect of M9 on breast cancer cell line MDA-MB-231 and observed that M9 has the ability to induce apoptosis and arrest cell cycle by affecting both PI3K/Akt/m-TOR pathway and Wnt/β-catenin pathway. It inhibits Akt thus downregulating the PI3K pathway74. Inhibitors of Akt are the foremost therapeutic intervention points that is observed to promote anti cancer effect in breast cancer cells. Such a study was done by Zhu et al., where they observed that the effect of AZD5363, an Akt inhibitor was successful in reducing stemness of the breast cancer cell line MCF-7. It was used in a combinatorial approach alongside 3,3’-diindoylmethane and it was also observed that the anti-cancer effect of the drug and induced DIM induced apoptosis in the cells75. Luminal A breast cancer cells are again a potential biomarker for modifying the phenotypic plasticity amongst the cells leading to aggressive and inducting resistance towards therapy. Dietary phytochemicals both alone and in an combinatorial approach has been used as a therapeutic modality targeting the luminal cells via modulating the key signalling pathways including PI3k-AKT-mTOR pathway, MAPK pathway, Notch pathway, Hedgehog pathway and others76.
Signal Transducer 3 and its upregulation in mediating cell plasticity and therapy resistance in breast cancer which makes it one of the potent targets for small molecule inhibitors and drugs. One such anti-cancer inhibitor, a natural phytoalexin, Resveratrol regulates the cascade of STAT signalling and has the potential to mitigate breast cancer progression77. Another study on anti-cancer drug resistance, trastuzumab which targets HER2+ cancer develops resistance in some patients. In order to circumvent this problem scientists have targeted proto-oncogene MUC1 which is one of the downstream targets of STAT378. 6Br-6a is a STAT3 inhibitor that has been evaluated as a therapeutic advancement as it inhibits STAT3 activation and induces inhibition towards cell proliferation, induce apoptosis and arrest of the cell cycle in breast cancer cells. Thus it can act as a promising target for breast cancer 79.
The use of molecules that inhibit the various constituents of the Wnt signaling cascade is currently being studied as a potential therapeutic strategy for Wnt-mediated cancers and as a mechanism to inhibit the therapy resistance conferred by this oncogenic signaling pathway. For example, the introduction of a truncated version of the APC protein was shown to have moderate success in mediating the degradation of beta-catenin in colorectal cancers, where the APC gene has a loss-of-function mutation. Another potential mechanism to elevate the beta-catenin degradation involves the increase in Axin production through the active inhibition of tankyrases, which as proteins that drive the degradation of Axin. Tankyrase inhibitors such as XAV939 have shown strong suppression of the Wnt/beta-catenin pathway, resulting in an anti-cancer effect in Wnt-mediated cancers64.
Given the prevalent role of the Hh signaling pathway in various types of cancers, its inhibition can be a strong contender as a potential therapeutic strategy. One major mechanism through which Hh pathway targeting therapies can be created is through the development of inhibitor molecules that target the pathway and silence it. For example, Smo inhibitors that target the Smo receptor have proved to be fairly successful. Two different Smo inhibitors, vismodegib and sonidegib, have received approval from the FDA for the treatment of BCC after it was found that these molecules were able to successfully bind to Smo and inhibit the downstream activation of the Hh target genes. Furthermore, more novel Smo inhibitors such as Saridegib and Taladegib are now under development, demonstrating the scope in the area of Smo inhibitor-based treatment mechanisms for several cancer types80. Moreover, cyclin-dependent kinase (CDK) inhibitors such as dinaciclib are also currently being tested in clinical trials against various types of cancer, including breast cancer. A recent study was able to show that the CDK inhibitors were able to reduce stemness and other malignant properties in TNBC cells by targeting the Hh signaling pathway81.
Targeted therapies involving the inhibition of the hyperactive Notch pathway in breast cancer are chiefly based on the use of gamma-secretase inhibitors, transcriptional inhibitors as well as the use of monoclonal antibodies to target the various ligand and receptor components of the Notch pathway. For example, in vitro studies with ER+ breast cancer cells showed that the use of the gamma-secretase inhibitor Z-Leu-Leu-Nle-CHO82 led to the strong inhibition of its growth. Similarly, the use of the monoclonal antibody OMP-59R583, designed to specifically target the Notch2 and 3 receptors has shown increased disease efficacy in clinical trials of triple-negative breast cancer. Furthermore, a study using a TNBC murine model showed that the inhibition of a deubiquitinase USP9x using a small molecule inhibitor called G9, reduces Notch activity84 and consequently remodels the tumor landscape and decreases tumor growth.
(Table 1)