Klarisa Rikova, Scientist, Cancer Biology
- Scientist, Cancer Biology
- M.S., University of Uzbekistan for Chemistry
Despite decades of research, cancer still kills millions of people each year. All cancers arise from mutations in key genes involved in cell proliferation, differentiation, and death. Over the past 25 years, about 300 such mutated genes have been discovered, however, genetic approaches are complicated by the difficulty of identifying a small number of causal changes within a sea of changes associated with genome instability. As a result, a need exists for strategies and methods which focus analysis on the key lesions driving disease.
The Cancer Biology group is taking advantage of PTMScan® technology, developed at Cell Signaling Technology (CST). This proprietary technology, which is described in a paper by John Rush [Rush, J., et al. (2005) Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat. Biotechnol. 23(1), 94–101.], which uses a CST™ Motif Antibody for immunoaffinity purification of peptides from digested cell extracts combined with LC tandem mass spectrometry to identify and quantify changes in post-translational modifications such as phosphorylation, acetylation, or ubiquitination.
When the group began this project in 2003 and focused on Profiling Tyrosine Kinases, very little was known about the oncogenes that drove some forms of NSCLC. In fact, 85% of the oncogenes in NSCLC were unknown. Today, through our work (Rikova K., et al. (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6), 1190–203.) and the work of others, that number has dropped to 65%. Work from our group has identified a number of new oncogenic drivers such as Met, PDGFRα, ALK, and ROS in NSCLC, which translates into 18,000 new cases per year in the U.S.
One very exciting finding from this study was the identification of a novel ALK-EML4 fusion protein in some NSCLC cell lines and tumors. We were very excited to discover this new ALK-EML4 fusion protein is highly phosphorylated in some forms of NSCLC. Epidemiological studies suggest that this fusion protein is found in a subset of 3–5% of all NSCLC patients. This equates to approximately 10,000 new cases per year in the U.S. These patients, who are often younger, non-smokers with a poor prognosis, benefit from cronzotinib, a drug developed by Pfizer.
We would like to extend our understanding of cancer biology by applying our technology to profile other signaling molecules and events such as Ser/Thr kinases and modifications like acetylation, methylation and ubiquitination, which allows us to construct deregulated signaling pathways in cancer patients.
Part of our company mission, and Klarisa's personal goal, is to make scientific contributions that lead to targeted cancer therapies with improved results and fewer side effects.
- Carretero J, Shimamura T, Rikova K, Jackson AL, Wilkerson MD, Borgman CL, Buttarazzi MS, Sanofsky BA, McNamara KL, Brandstetter KA, Walton ZE, Gu TL, Silva JC, Crosby K, Shapiro GI, Maira SM, Ji H, Castrillon DH, Kim CF, García-Echeverría C, Bardeesy N, Sharpless NE, Hayes ND, Kim WY, Engelman JA, Wong KK (2010) Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell 17(6), 547-59.
- Guo A, Villén J, Kornhauser J, Lee KA, Stokes MP, Rikova K, Possemato A, Nardone J, Innocenti G, Wetzel R, Wang Y, MacNeill J, Mitchell J, Gygi SP, Rush J, Polakiewicz RD, Comb MJ (2008) Signaling networks assembled by oncogenic EGFR and c-Met. Proc. Natl. Acad. Sci. U.S.A. 105(2), 692-7.
- Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6), 1190-203.