Saturday, June 7, 2014

Mechanisms For Trastuzumab Resistance

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.    

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.