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RESISTANCE TO ANTI-HER2 THERAPIES IN BREAST CANCER
Resistance to Anti-HER2 Therapies in Breast Cancer
Mothaffar F. Rimawi, MD, Carmine De Angelis, MD, and Rachel Schiff, PhD
OVERVIEW
HER2 is amplified or overexpressed in 20% to 25% of breast cancers. HER2 is a redundant, robust, and powerful signaling pathway
that represents an attractive therapeutic target. Anti-HER2 therapy in the clinic has resulted in significant improvements in patient
outcomes and, in recent years, combinations of anti-HER2 therapies have been explored and carry great promise. However, treatment
resistance remains a problem. Resistance can be mediated, among others, by pathway redundancy, reactivation, or the utilization of
escape pathways. Understanding mechanisms of resistance can lead to better therapeutic strategies to overcome resistance and
optimize outcomes.
HER2 is a member of a membrane tyrosine kinase receptor
family (HER1–4). Although HER2 does not have
any known ligands, there are more than 10 different ligands
that activate other family receptors (Fig. 1). 1-7 On binding,
ligands induce receptor homo- and heterodimerization activating
a phosphorylation-signaling cascade. HER2 in cancer
cells can be activated by either heterodimerization with other
ligand-bound HER family members or, when overexpressed,
by homodimerization. 8 The resulting downstream signaling
regulates transcription of genes responsible for cell proliferation,
survival, angiogenesis, invasion, and metastasis. 1-4,6,9,10
HER2 is amplifıed or overexpressed in 20% to 25% of breast
cancers and results in aggressive behavior with rapid growth
and frequent metastasis. Therefore, targeting HER2 represents
an attractive treatment option, and that approach has
been successful in the clinic.
The fırst targeted therapy against HER2 was the humanized
monoclonal antibody trastuzumab. The mechanism of
action of trastuzumab is not completely understood but it interacts
with the extracellular domain of HER2 to inhibit its
function. Trastuzumab has been suggested to inhibit signaling
from HER2 homodimers better than heterodimers with
HER1 (epidermal growth factor receptor [EGFR]) or
HER3. 11-13 The resulting downregulation of the PI3K/AKT
pathway signaling leads to induction of apoptosis in human
tumors. 6,9,14 Trastuzumab has also been shown to work in
part by inducing antibody-dependent cellular cytotoxicity.
Although trastuzumab combined with chemotherapy reduces
the risk for recurrence of HER2-positive tumors, many
patients have tumors that exhibit de novo or acquired
resistance. 15-18
Many mechanisms for resistance to anti-HER2 therapy
with trastuzumab have been suggested. 18,19 Those broadly
fall under three major categories. The fırst category is redundancy
within the HER receptor layer: the ability of the pathway
to continue to signal despite being partially inhibited
because of redundant ligands and receptors that enable alternative
dimerization patterns. The second category is reactivation:
the ability to reactivate pathway signaling at or
downstream of the receptor layer such as with activating
HER or downstream mutations, or loss of downstream pathway
negative-regulating mechanisms. The third category is
escape: the use of other pathways, which may pre-exist or be
acquired at the time of resistance, but are not usually driving
the cancer cell when HER2 is uninhibited. For purposes of
this review, we will give an example from each of those resistance
categories, focusing on mechanisms of resistance that
have been best explored preclinically and in clinical trials: incomplete
receptor family inhibition as an example of redundancy,
deregulation of the PI3K pathway as an example of
reactivation, and the role of the estrogen receptor (ER) in resistance
as an example of escape. Additional roles for multiple
other pathways and mechanisms involved in intrinsic and
acquired resistance to HER-targeted therapy, including various
receptor and cellular tyrosine kinases (e.g., MET,
IGFR-1, c-SRC, and EphA2), 19-23 mucins, 24 regulators of cell
cycle and apoptosis 19,25-27 and various elements of the tumor
microenvironment and the host immune system, 28-31 have
been recently thoroughly reviewed, 18 and are beyond the focus
of the current paper.
INCOMPLETE RECEPTOR FAMILY INHIBITION
One mechanism for resistance to anti-HER2 therapy is incomplete
blockade of the HER receptors. This occurs when
the drug or drugs used do not effectively block signaling from
From the Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, TX.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Mothaffar Rimawi, MD, Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza BCM600, Houston, TX 77030; email: rimawi@bcm.edu.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
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