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Page 2 of 14 Ansari et al. J Cancer Metastasis Treat 2019;5:20 I http://dx.doi.org/10.20517/2394-4722.2018.68

INTRODUCTION
Brain metastases represent a significant clinical challenge for the treatment of patients with human
epidermal growth factor receptor 2 (HER2)-positive breast cancer. Although modern multimodality
therapies have improved the survival of patients with primary breast cancer and systemic metastases, the
[1,2]
overall median survival of patients with brain metastases is dismally less than one year . Furthermore,
as the brain represents a “sanctuary site” for HER2+ metastases, and has comprised a larger proportion
[3,4]
of relapse sites over time . Despite this increasing incidence, there is no current consensus on therapy
[5,6]
for those with intracranial progression . Current clinical options for HER2+ brain metastases patients
are limited to trastuzumab (anti-HER2 monoclonal antibody) treatment in conjunction with whole-brain
[7]
radiotherapy or stereotactic radiosurgery , neither of which clinically effective in treating life-threatening
brain metastases that often lead to severe cognitive complications.

The poor prognosis of breast cancer brain metastatic (BBM) patients with local therapies underscores the
need for better systemic treatments. Over the last few years, preclinical and clinical progress in the treatment
of BBM has led to novel hypotheses for improving therapeutic outcome. The limited efficacy of trastuzumab
[8]
against BM is often attributed to an inadequate penetration through the BBB . Lapatinib, a small molecule
kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, was evaluated in BCBM due to
its ability to better penetrate the BBB than trastuzumab [9,10] . The success of lapatinib and capecitabine in
preventing brain metastasis led to its inclusion in patients with established brain metastases. New generation
ErbB family inhibitors neratinib and afatinib are more potent and specific than lapatinib, showed significant
[11]
responses in limited cases of BBM . The downstream HER2 signaling inhibitors including the PI3K
inhibitor BKM120 and the mTOR inhibitor everolimus were evaluated to overcome de novo or acquired
resistance to anti-HER2 therapy. Indeed, targeting the HER2 family member HER3, critical for HER2
downstream signaling, enhances the efficacy of HER2-targeted therapies in preclinical models of BBM [12,13] .

Recent clinical findings described the efficacy of antibody-based therapy in BBM. Upon treatment
Bevacizumab and trastuzumab-DM1 adequately accumulate in brain metastatic lesions to exert positive
effect [14-17] . Antibody-chemotherapy conjugate such as ado-trastuzumab emtansine (T-DM1) was approved
for the treatment of HER2-positive breast cancer due to its higher efficacy over lapatinib and capecitabine
[18]
in patients with disease progression after trastuzumab . As T-DM1 targets acquired or microenvironment-
mediated activation of Her2 independent signaling pathways, this agent would be expected to be effective in
such patients.

Using RNA sequencing (RNA-seq) analysis of primary HER2+ breast cancer and HER2+ breast to brain
metastatic tumor resections, along with normal breast and normal brain tissues, we demonstrated that
SRC- and ERBB2-mediated regulation of PI3K-AKT/mTOR signaling plays a critical role in BBM cell
[19]
proliferation . Inhibition of SRC, ERBB2, and downstream kinases induced robust apoptotic cell death.
In parallel experiments, we conducted a high throughput screening of 1650 clinical and preclinical drug
candidates and found that activation of GABA signaling using a GABA agonist induces apoptosis in the
breast to brain metastatic cells.

Interestingly, it has been shown that the SRC family of non-receptor tyrosine kinases is critical for both
[20]
HER2+ and triple-negative breast cancer . SRC activation maximizes the HER2: HER3 interaction and
serves as a convergent point of multiple downstream signals, including the PI3K-AKT/mTOR pathway, thus
regulating cell viability [20,21] . Similarly, activation of GABA signaling negatively regulates not only neural
stem cells but also embryonic and cancer stem cells [22-24] . GABAergic breast to brain metastatic cells rely
on GABA as an energy source, and activation of GABA signaling prevents cell proliferation directly or by
blocking the supply of GABA to the invading cells. This collective evidence suggests that inhibiting HER2
and simultaneous targeting SRC and/or GABA is a promising strategy for the treatment of breast cancer
brain metastasis.