HDAC is also shown to occur in an inhibitor

by Selleckchem | Oct 24 2012

These include KIT, RET, STK11 LKB1. These are all known cancer associated kinases that have dysregulated signaling in various human cancers, including GIST and hematological malignancies, papillary thyroid cancer and lung cancer. Discussion In the era of HDAC molecularly targeted therapeutics in cancer therapy, the impact of cancerassociated mutations on kinase inhibitor sensitivity resistance has increasingly important implications in the success of novel targeted inhibitors such as erlotinib. Furthermore, knowledge of mutational correlation with inhibitor sensitivity resistance would likely facilitate more effective and personalized targeted therapeutics development in cancer therapy. The clinical course of the patient where the somatic E884K mutation was identified suggested that different mutations of a target kinase, such as EGFR, may lead to differential responses to targeted kinase inhibitors.
Alternatively, one Aurora Kinase may postulate that there might be differences in cerebrospinal fluid penentrance by TKIs that could potentially account for central nervous system failure with disease progression in the compartment on therapy. Our biochemical studies here now show that E884K mutation in cis with L858R differentially altered inhibitor sensitivity when compared to L858R alone, through differential inhibition of the pro survival AKT and STAT3 signaling pathways associated with altered induction of cleaved PARP. This is also shown to occur in an inhibitor specific manner within the class of various ERBB family small molecule inhibitors, including reversible single EGFR or dual inhibitors and irreversible EGFR inhibitor.
Moreover, the E884K alone and L858RE884K double mutant EGFR remained sensitive to EGF, and the E884K mutation cooperates with L858R when in cis to enhance the mutational effects on downstream phosphoprotein activation. To date, essentially all mutational combinations involving L858R studied were found to exist in cis, suggesting potential cis mutation to mutation cooperation in EGFR signaling and possibly tumorigenesis. Interestingly, the double mutation, L858RE884K conferred a distinctly more sensitive response to EGF stimulation selectively in the MAPK ERK1 2 cell proliferation pathway compared to either wild type, E884K alone or L858R alone. Hence, the double mutation L858RE884K modulated downstream EGFR signaling differentially with distinctly different effects on the AKT and MAPK ERK1 2 phosphorylation.
Moreover, E884K had a dominant effect over L858R, when in cis, in these signaling modulatory effects. E884K, alone or in cis with L858R, can also mediate induction of p STAT3 , and may have a role in differential regulation of STAT3 activation and thus nuclear translocation for transcriptional activity. Our data also share some similarities to the recent findings that various activating gain of function mutations of FLT3, while all induced FLT3 kinase activation constitutively, they showed differential downstream signaling activation.