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)