Cancer has been a troubling medical condition in the recent past given that it has no particular treatment. More and more people are getting diagnosed with cancer by the day and the statistical data keeps rising. In 2016, it had been reported that an estimated number of 1,685,210 new cases of cancer would be diagnosed. The estimated number of deaths was expected to be close to 600,000, which is quite a devastating number (American Cancer Society, 2017). Nonetheless, most of the people who end up surviving the condition have some of their body parts cut off. The most common forms of cancer experienced today are breast cancer, prostate cancer, blood cancer, thyroid cancer, and pancreatic. Whereas cancer has no sue treatment yet, medical professionals have indicated that it can be stopped from occurring. Propositions have been made for people to avoid feeding on foods that are highly laced with chemicals and also to exercise from time to time to maintain fitness. This paper looks at how the allosteric inhibition of the SHP2 phosphatase inhibits cancer that arises as a result of tyrosine kinases by providing a summary of the research conducted by Chen et al. (2016).
The Research Question
In this study, Chen at al. (2016) wanted to find a new way of lowering the rate of cancer developments in the world. They thus set out to investigate how inhibiting SHP2 phosphatase was a viable way of reducing the chances of the onset of cancer in human beings. The research question being asked was: does the allosteric inhibition of the SHP2 phosphatase inhibit cancer that comes from tyrosine kinases?
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Hypothesis : The use of the SHP099 as an inhibitor to the SHP2 is a viable strategy for mitigating the proliferation and growth of cancer cells.
Why it is an Interesting Topic to the researchers
The reason why the group of researchers were interested in finding out if this hypothesis was true is because of the threat that cancer poses to the society not only today but also in the future. As it was aforementioned, cancer has no discovered treatment method. The only way that cancer can be mitigated as of today is through taking prevention measures, with the inhibition of the SHP2 being one of the preventive measures, as hypothesized. The increased number of deaths as a result of cancer was also a powerful trigger that pushed them to look inside the issue. Nevertheless, cancer has for a long while be found to result from careless living of most people. Poor health measures, poor diet, and failure to engage their bodies in exercise have been the most common causes of cancer. In realizing that worrying about treatment is of no help, the researchers came up with this new hypothesis as a way of reducing the rate of cancer development or even countering it in its early stages.
A Brief Overview
The report on their research starts off with a detailed description of what the SHP2 is and its main function in the body systems. They delve deep into explaining how the activation of mutation of the SHP2 is a causative agent of cancer. As it is explained in the report, the activation of mutation of the SHP2 results in some adverse pathological conditions such as the Noonan syndrome. Most of these pathologies that result from these mutations have been found in individuals suffering from various cancer types such as leukemia, lung cancer, and breast cancer. Further, the SHP2 is also said to be responsible for the survival and proliferation of body cells which it is able to do once the RAS-ERK signalling pathway becomes activated. Significantly, if the SHP2 activity is reduced in the body, cancer cells are bound to be suppressed and this acts as a way of providing treatment for cancer, especially if it is diagnosed in its early stages.
Methods Used and Results
To predetermine how the effect of SHP2 on cancer, Chen et al. (2016) performed the screening of over 7,500 genes which had 20 short hairpin RNAs each. Once the genes were obtained, Chen et al. (2016) screened them across 250 lines of cells that had been obtained from the Cancer Cell Line Encyclopaedia (CCLE). After a correlation analysis was done, it was found out that the cell lines that displayed sensitivity to the depletion of SHP2 were the most sensitive to the depletion of EGFR. On the other side, when another subset of lines, especially those that depend on a receptor of tyrosine kinases that is known, were found to display a specific kind of correlation to the depletion of SHP2. From these developments, it was evident that RTK cells had a full dependency on the SHP2 for their survival. The rest of the cells that displayed random sensitivity to KRAs and NRAs were found to have a minimal impact on the SHP2.
With the aim of substantiating their theory, they further introduced doxycycline (dox)-inducible SHP2 shRNAs to lines of cancer cells that had RTK alterations that were distinctive. In this case, each of the RTK-dependent cancer cells were directly affected by the depletion of the SHP2. This kind of change was only notable in the cells that were RTK-dependent. For the rest of the cells that were BRAF and KRAS-mutated, there was no growth effect detected when the depletion of SHP2 was witnessed.
Following this finding, the researchers then went ahead to investigate how the catalytic activity of the SHP2 was significant in the growth and development of cell lines that were entirely sensitive. This was done through the conducting of a complementation experiment. They re-expressed “shRNA-resistant alleles of wild-type SHP2 or the catalytically inactive SHP2C459S variant in MDA-MB-468 cells.” Once this was done, Chen et al. (2016) realized that the depletion of SHP2 was an inhibitor to the growth of MDA-MB-468 and was characteristically followed by the reduction p-ERK levels. When the dox treatment was instituted, it was found out that both the wild-type SHP2 and the SHP2C459S expressed themselves at the same levels. The wild type SPH2, however, was found to have a restoration effect of the p-ERK levels as well as cell growth. As for the SHP2C459S, there was no significant amount of cell growth and p-ERK levels noted. These new findings prevented a furthered way of thinking that suggested the phosphatase activity of the SHP2 was essential for the realization of p-ERK activation and the maintenance of cell development in cancers that are driven by RTK.
Further, the researchers also came up with a hypothesis that cells which had an activated and constitutive RAS signaling were insensitive to the inhibition of the SHP2. In a quest to substantiate this new hypothesis, SUM52 cells that were dependent on the SHP2 were subject to a lentivirus that was carrying the oncogene KRASGI2V for transduction. Once the transduction had taken place, it was noted that upon expressing the KRASGI2V p-ERK levels were restored and the cells ultimately became insensitive to the depletion of the SHP2. Nonetheless, the eventual depletion of the SHP2 was found to have little or no impact on the proliferation and cell growth of the MDA-MB-231 (KRASG13D) cells as well as the A2058 (BRAFV600E) cells. The conclusion that they derived from this experiment was that cancer cells were refractory to the SHP2 inhibition, especially those with an oncogenic RAS/RAF mutation.
Conclusions Made
From this experiments and the results obtained, it was found out that there was a relation between the SHP2 and the development of cancer in individuals. As a result, the group of researchers concluded that inhibiting the mutation of the SHP2 was a way of reducing the growth and development of cancer cells. With the use of a highly potent (IC50=0.071 µM) inhibitor, the SHP099, which is defined as selective and orally bioavailable, the levels of SHP2 in the human body were stated to be lowered in very significant amounts such that cancer cells could no longer experience growth.
How does the experiment fit into the project?
The experiments conducted by Chen et al. (2016) are very necessary and draw some very key guidelines that will be used to provide for future advancements in the fight against cancer. The end goal of the project is to ensure that cancer infections are minimized in the most ways possible so as to reduce the number of deaths and mutilations that come with the condition. Therefore, with such a discovery having been made, the researchers have an edge on which they can build ways of mitigating cancer in the world.
View on the Paper
The paper was well written and the researchers developed their ideas in a very constructive manner. First and foremost, the large group of researchers are all individuals with vast experience in the field of cancer as well as body systems and operations. They started off by explaining what the SHP2 is and the role it plays in the human body. Thereafter, they showed how its mutations and increased levels in the human body is a factor for the growth of cancer cells and how its depletion is necessary to limit cases of cancer. However, the paper was written an entirely scientific way. It can only be understood by professionals who have vast knowledge in the field. For the common people, not much of what is written in the paper could make sense to them and this could result in a misunderstanding or the lack of flow of information which they hoped would reach to the public. Moreover, if at all the concept being presented in the paper is to be effective, they should find a way to make it less ambiguous and more understandable.
Conclusion
As it was mentioned at the beginning of the paper, cancer is very deadly and thus requires people to exercise a lot of sobriety in regards to the issue. If cancer is to be fought successfully today, the public needs to be enlightened more on the infection and ways in which it can be evaded. This will help in reducing the worry about the number of people who are prone to falling victims of the condition and having some of their body parts removed or even ending up dead. The allosteric inhibition of the SHP2 through the use of SHPO99 has been shown to be an effective way in which cancer cells can be killed. If individuals were to take this inhibitor, cancer cases would drastically go down over the next few years as Chen et al. (2016) observed. However, there is a need for further research to be conducted in light of the same issue so as to ensure that the most conclusive solutions are obtained. There might not be a cure for cancer today, but as the medical saying goes, prevention is better than cure.
References
American Cancer Society. (2017). Cancer Facts & Figures 2016. Retrieved from https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016.html.
Chen, Y., LaMarche, M., Chan, H. et al. (2016). Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature, 535 (7610), 148-152.
