KSP secondary drug resistance Overcome T790M mutations Ren

Mas after treatment with HKI 272nd KSP In vitro studies, however, at concentrations of 1 amol / l or more, while the dose-limiting toxicity, w t, as in a phase I clinical study recently completed HKI determined 272: F0.2 Amol / L. Thus, is m possible that HKI 272 can overcome T790M only at relatively high doses m not sure resembled that to reach patients. To test this directly, a dose-response curve was at 272 HKI in NIH3T3 cells expressing F done Is steady or wild-type EGFR T790M EGFR. Tats Chlich was 0.2 amol / l HKI 272 is sufficient in order to EGFR phosphorylation cells, inhibit the wild-type EGFR, but not in cells that EGFR T790M. Remarkably, T790M EGFR protein shows an h Heres levels compared to basal phosphorylation of EGFR wild-type and best CONFIRMS published earlier results VER. Our results suggest that the efficacy of this drug in a concentration observed in vitro requires m Not legally possible to reach patients by Arzneimitteltoxizit t, and therefore not effectively inhibit EGFR HKI 272 T790M clinically achievable concentrations. Thus there is clearly a need, an EGFR inhibitors develop st Amplifier irreversibly, with potentially reduced toxicity of t, with secondary drug resistance Overcome T790M mutations Ren. Furthermore, these results suggest that the use of HKI 272, a first-line treatment, T790M EGFR-TKI progression of the disease Similar is found as with reversible EGFR inhibitors. The BX-912 702674-56-4 substitution of cysteine 797 resistance to irreversible EGFR EGFRInhibitor Previous studies have shown that effective control of the EGFR T790M mutant signaling by relatively high concentrations of HKI 272, suggesting that EGFR inhibitor-st Irreversible amplifiers can be effectively acquired in the hospital TKI resistance.
Remarkably, many of these irreversible inhibitors tested in clinical trials. If any of these prove to F Ll be strong enough to overcome resistance to gefitinib / erlotinib with T790M at pharmacologic concentrations, there will always be important, secondary Re-resistance mechanisms, which w Occur during treatment with these inhibitors anticipate . This was also illustrated by the experience with dasatanib as second-line treatment for leukemia Myelo chemistry Chronic imatinib resistance has developed. Therefore expect different mechanisms of resistance to the EGFR kinase inhibitor irreversibly, we investigated the potential of the r The cysteine residue in the kinase-Dom Ne of EGFR binds covalently to the HKI 272. As with gefitinib and erlotinib 272 HKI binds EGFR within its ATP-binding pocket. But in contrast to gefitinib and erlotinib, HKI 272 is a covalent bond with a sulfhydryl group of cysteine of EGFR 797th We assume that the substitution of this cysteine residue would be reduced in an F Ability HKI 272 to inhibit EGFR, leading to HKI 272 resistance. To this M Opportunity to test, we generated a variant in which cysteine 797 to alanine EGFR GE Changed, either in a background Pazopanib of wild-type EGFR, L858R background or the background was Del15. W While wild-type EGFR, L858R or Del15 have tats Chlich inhibited HKI 272 concentrations as low as 0.02 amol / L, EGFR variants C797A, and C797A/L858R C797A/Del remaining.

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