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cells escape anti-HER2 therapies is through the expression of p95HER2. Approximately 30% of HER2-
positive breast cancers express the p95HER2 fragment, which is a truncated form of HER2 that is especially
oncogenic, as it spontaneously homodimerizes into a constitutively active form. Tumors with p95HER2
fragments are resistant to trastuzumab because they lack the extracellular domain and the binding site
for trastuzumab [53,54] . Unlike trastuzumab, HER2 RTK inhibitor lapatinib can inhibit p95HER2 along with
HER2, as it binds the ATP active site present in both proteins. This inhibition blocks phosphorylation and
[55]
inhibits downstream signaling .
Although lapatinib has some advantages, cancer cells can still develop resistance. When HER2 signaling
is suppressed by lapatinib and trastuzumab alike, alternative survival mechanisms can be activated. Even
though HER2 and p95HER2 are shown to be inhibited by lapatinib, the suppression of HER2 signaling
can lead to the upregulation of other HER family members and RTKs, such as the fibroblast growth
factor receptor-2 and insulin-like growth factor-1. Alternately, lapatinib resistance can be attributed
to the hyperactivation of the PI3K pathway by the activation of Src kinases through insulin receptor
substrate 4. Recently, another anti-HER2 agent, neratinib, was evaluated in clinical trials. Unlike lapatinib,
[56]
neratinib is an irreversible pan-HER inhibitor . A recent phase III clinical trial compared the effects of
neratinib versus lapatinib in combination with capecitabine, an antimetabolite, in patients with HER2-
positive metastatic breast cancer. The results indicate that neratinib + capecitabine significantly improved
progression-free survival over lapatinib + capecitabine. These results offer a promising outlook on the use
[57]
of neratinib combination therapy in the treatment of aggressive HER2-positive breast cancers .
Trastuzumab and lapatinib-resistant cells continue to depend on HER2 to evade drug treatment. One way
in which these late stage drug-resistant cancer cells continue to depend on HER2 is by expressing MUC4,
a membrane-associated mucin that masks HER2. This is shown to prevent the binding of trastuzumab to
HER2 and to maintain HER2 phosphorylation. Knockdown of MUC4 with RNA interference (RNAi) led to
[58]
an increased binding of HER2 to trastuzumab . Studies have also been designed to investigate the use of
RNA interference directly against HER2. The results of a recent study demonstrate that RNAi of HER2 by
siRNA has antiproliferative effects and decreases HER2 mRNA and protein levels in vitro [59,60] . In addition,
another study looked at the effects of siRNA on BT474 cells (ductal carcinoma). The authors report that
siRNA treated BT474 cells do not acquire resistance against the treatment. This work has not yet been
translated to in vivo studies, but these preliminary results demonstrate that siRNA poses as a promising
[61]
option for patients with drug-resistant HER2-positive breast cancer .

PI3K/AKT/MTOR PATHWAY
The mammalian target of rapamycin (mTOR) pathway is another example of an important signaling
protein that can operate activated downstream to RTKs [Figure 3]. mTOR is a serine/threonine kinase.
Together with other proteins, it forms two different complexes, mTOR complex 1 (mTORC1) and mTOR
complex 2 (mTORC2). mTORC1 is activated by RTKs as well as by other types of stimuli. It is part of a
signaling pathway that includes phosphoinositide 3-kinase (PI3K) and AKT, which are implicated in cell
survival [Figure 3]. The mTOR pathway is activated in a wide variety of solid tumors and is one of the
main causes of resistance to anti-tumor therapies. The mTORC1 signaling cascade is involved in growth,
proliferation, motility, metabolism, and immune response regulation. Hyperactivation of the PI3K/AKT/
mTOR pathway leads to genomic instability and uncontrolled proliferation of cancer cells. Thus, due to its
role in tumorigenesis and drug resistance, the PI3K/AKT/mTOR cascade is a prominent therapeutic target
for several types of cancers .
[62]

PI3K is an important upstream activator of mTORC1. The PI3K family is a group of lipid kinases that
regulates a broad array of cellular functions in signaling and metabolism. Of the 3 classes of PI3Ks, the
class I PI3Ks are most often linked to oncogenesis . The activation of G-coupled protein receptors
[63]