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achieve a greater therapeutic response [216,218,219] . Below we will address additional potential therapeutic avenues
one may use to dismantle E-M/CSC plasticity in order to prevent metastatic dissemination, secondary site
outgrowth, or re-sensitize cancer cells to standard of care therapies.

TARGETING MALIGNANT POPULATIONS
STAT3
STAT3 is persistently activated in cancer cells, as it is a downstream effector of several receptor tyrosine
kinases (RTKs) commonly activated by growth factors and cytokines [220-222] . We, as well as others have
demonstrated that, persistent STAT3 activation in cancer cells induces mesenchymal and CSC properties,
inhibits apoptosis, and maintains a more un-differentiated phenotype [12,14] . Therefore, STAT3 is a promising
therapeutic target. A number of small-molecule inhibitors of STAT3 (KI16; BP-5-087; WP1066) are currently
in development and combination therapies, with BCR-ABL1 or BRAF inhibitors, have shown positive results
in the treatment of several cancer types [223-225] . In the context of TNBC, a recent phase Ib/II study combining
the cancer stemness inhibitor Napubacasin (BB608), which prevents STAT3 activation, with weekly
administrations of paclitaxel showed improvement in metastatic patients whose cancer had progressed
while on a taxane-based regimen (NCT01325441).

PI3K, Akt and mTOR
The PI3K/Akt/mTOR pathway is involved in several cell processes, including proliferation, metabolism
and motility, therefore it is not surprising that its dysregulation corresponds to uncontrolled proliferation
and propagation in a wide spectrum of cancers. The role of the PI3K/Akt/mTOR pathway in maintaining
cell plasticity in cancer has been documented in several publications [226-228] . In the context of breast cancer,
PIK3CA mutations have been observed in each of the different subtypes, but mostly in hormone receptor-
positive tumors where it’s associated with disease progression and resistance to endocrine therapy. Each
PIK3CA mutation results in an abnormal activation of the alpha subunit of PI3K, that with the beta subunit
is the most common in breast tissue . PIK3CA mutations appear to hold prognostic and predictive value
[229]
in hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Several studies show
how targeting tumors carrying a PIK3CA mutation with PIK3CA inhibitors increased the PFS of patients .
[230]
In January 2019, results from the phase III SANDPIPER clinical trial (NCT02340221) were posted. This
international, multicenter, randomized, double-blinded, placebo-controlled study was designed to test the
efficacy of a combo of the PIK3CA SMI taselisib and the synthetic estrogen receptor antagonist fulvestran
versus placebo and fulvestran in the treatment of ER-positive, HER-2-negative locally advanced or metastatic
breast cancer harboring a PIK3CA mutation in patients with disease recurrence after or during treatment with
aromatase inhibitor (AI). SANDIPIPER is the first placebo-controlled trial testing the efficacy of a mutant-
specific PI3K inhibitor . Taselisib is specifically directed against the alpha isoform of PIK3CA, however
[231]
it can inhibit the gamma and delta isoforms as well, thus causing an increase in toxicity mostly involving
the gastro-intestinal tract. Another phase III clinical trial, BELLE-2 (NCT01610284) is analyzing the effects
of the pan-PI3K inhibitor buparlisib in combination with fulvestran compared to fulvestran and placebo
combo. Unfortunately, also buparlisib showed important side effects, particularly hyperglycemia . Several
[229]
other PI3K inhibitors are currently under investigation in clinical trials, including apelisib (NCT02437318 -
SOLAR-1), which showed encouraging clinical benefits in the majority of patients enrolled . In the future,
[232]
research efforts should be more focused at inhibiting exclusively the alpha subunit of PIK3CA, thus reducing
the risk of toxicity and side effects. Interestingly, GDC-0077 from Genentech appears to be extremely more
specific towards the alpha subunit of PIK3A over other subunits, thus representing a potentially less toxic
alternative to other inhibitors and is currently investigated in a phase I clinical trial alone or in combination
with other agents, such as palbociclib, letrozole and fulvestran (NCT03006172).

While the role of mTOR signaling in promoting a CSC phenotype is still controversial, its activation in BC
appears to be essential for colony formation in vitro and tumorigenicity . Furthermore, mTOR signaling
[233]