My cancer project looked at a possible mechanism for Trastuzumab
resistance, this being AMF causing HER2 phosphorylation leading to
intracellular signaling. While this idea is interesting it is fairly new so I
wanted to do more research on what is widely accepted today as the mechanism
for Trastuzumab resistance. Trastuzumab is a monoclonal antibody that
specifically targets the HER2 receptor. A monoclonal antibody is a synthetic
molecule whose primary role is to attack a certain defect in a cancer cell. These
antibodies also cause cancer cells to become more visible to the immune system,
thereby causing an immunogenic response. Trastuzumab binds to HER2 extracellularly
and this causes HER2 to become deactivated. This ceases all signal
transduction, which leads to inhibition of both the MAPK pathway and the pi3k
pathway. However, the majority of patients with metastatic breast cancer
develop a resistance to Trastuzumab within a year. How does this happen?
While the exact mechanisms
for Trastuzumab are still being researched there are some molecular and
cellular mechanisms that have been reported in the literature. The first
mechanism by which Trastuzumab resistance occurs is through disruption of the
interaction between the therapeutic drug and the target receptor. MUC4 is a
high molecular weight glycoprotein. It is known for it's anti-adhesion
properties, as well as its direct link to metastasis. This membrane-bound
glycoprotein was shown to bind to HER2 and cause steric hindrance, leading to
an inability for Trastuzumab to bind to the receptor. MUC4 interacts directly
with HER2, and subsequently this interaction is dependent upon an epidermal growth factor (EGF)-like domain on the
ASGP-2 subunit of MUC4. Due to this interaction MUC4 acts as a ligand for the
HER2 receptor and causes phosphorylation, and therefore the downstream
signaling cascades. Another conclusion researchers were able to make was that
levels of MUC4 are inversely correlated with Trastuzumab binding
capabilities.
Trastuzumab
resistance has also been credited to increased signaling from the insulin-like
growth factor I-receptor(IGF-IR). Increased IGF-IR levels were shown to reduce
Trastuzumab effectiveness, and, similar to MUC4, IGR-IR also interacts directly
with HER2 and causes phosphorylation. Another side effects is that in
Trastuzumab resistant cells, IGF-IR causes a more rapid stimulation of Pi3k and
MAPK pathways. The researchers also observed down-regulation of p27kip1
in cells which had
increased levels of IGF-IR. They concluded
that, "p27kip1 is a critical mediator of Trastuzumab response, and
that its down-regulation may occur subsequent to increased signaling from
growth factor receptors such as IGF-IR, promoting resistance to
Trastuzumab."(Nahta 2006).
Trastuzumab
resistance is a major problem, and understanding the biological and molecular
reasonings for this resistance is vital in finding a solution to this
resistance. There are some therapies, which tackle the problems stated above.
Firstly, there is Pertuzumab, which is similar to Trastuzumab in that it is
also a monoclonal antibody, and is a dimerization inhibitor. However,
Pertuzumab disrupts the interaction between IGF-IR and HER2 in Trastuzumab
resistant cells. Pertuzumab binds to domain I,II, and III, while Trastuzumab
binds to domain IV of the extracellular domain. While all this information is
promising there still seems to be a significant number of patients who become
resistant to Pertuzumab and Trastuzumab. The researchers believe that
downstream signaling may be causing the resistance. More research would be
needed in figuring out the mechanism by which cancer cells gain resistance to
Pertuzumab.
As Trastuzumab resistance becomes a more important
issue, and as recent research strongly supports the role for Trastuzumab not only in
management of metastatic cancer but also as an adjuvant therapy in HER2
positive breast cancer. Detecting the molecular and biological
mechanisms that lead to Trastuzumab resistance is of vital importance. Not
until we find a therapy that specifically targets these mechanisms can we
produce a Trastuzumab therapy that lasts a sufficient amount of time.
Sources:
Hudis, Clifford A.
"Trastuzumab — Mechanism of Action and Use in Clinical Practice." New
England Journal of Medicine 357.1 (2007): 39-51. Web.
Nahta, Rita. Esteva, Francisco. “HER2
therapy: Molecular mechanisms of Trastuzumab resistance.”
Biomed Central Study. (2006): 0.1186/bcr1612. Web.
