Groundbreaking Study Demonstrates How Kinases May be the Key to the Prognostication and Treatment of
A recent Nature Communications article summarizes how 6 kinases have been isolated that demonstrate both predictive value and potential targets for the treatment of triple negative breast cancer. Although the study is small, the findings may provide profound insight into a cancer that until now has been difficult to categorize (TNBC is actually a lump name for many breast cancers that do not express estrogen, progesterone, or HER2 receptors).
Kinases are enzymes that catalyze the transfer of phosphate groups from high-energy donating molecules to specific substrates such as the amino acids serine, threonine, and tyrosine. The phosphorylation of proteins is an important mechanism of cell signaling as it directly alters the target protein's level of activity. Please see Kinase on Encylopaedia Britannica online. There are many kinases found in the cells of TNBC tumors. This group was able to pinpoint the critical kinases involved in TNBC activity by utilizing mass spectrometry of TiO2-IMAC-purified phospho-fractions, which can cover a greater range of phosphoproteomics. KSEAS technology allowed for summaries of the driving kinases involved in large phosphoprofiles. Findings revealed that if one or more of specific kinases were found to be hyperactive, the patient demonstrated a 9.5 fold higher relapse risk. Based on their data, the predictive hyperactive kinases include PRKCE, c-Kit, p-ERK (Thr202/Tyr204), p-P70S6K (Thr389), p-PNKP (Ser114/Thr118), and CDK6.
They also tested three clinical-grade agents (palbociclib, imatinib, and GDC-0994; which target CDK628, c-Kit29, and ERK30, respectively) and three non-clinical-grade agents (A12B4C3, the peptide H-EAVSLKPT-OH. and Ly2584702; which target PNKP31, PRKCE32, and P70S6K33, respectively) on tumor lines in vitro. When used alone, agents demonstrated little in vitro activity. However, when researchers combined 2 agents, they observed profound inhibitory effects in the MDA-MB-231, MDA-MB-468, and Hs-578T cell lines. This study has the potential to fuel the classification, understanding, and treatment of TNBC for years to come.
If you're interested in more on this, please also see my article on mTOR, a serine/threonine kinase that acts downstream of the kinases mentioned above. Please also see information relating to the CLEVER trial offered by Dr. DeMichele at the University of Pennsylvania Medical Center.