Acute Myeloid Leukemia (AML) is generally addressed by a chemotherapy regimen, however, this method of treatment is highly nonspecific and a relapse of the disease occurs in a majority of patients. Due to the nonspecific nature of the chemotherapy drug, it is hypothesized that chemotherapy temporarily solves the problem and fails to completely eliminate the the cancer stem cells, which harbor the potential for self-renewal and continuous proliferation. This has lead to the need for a better drug and therefore an explosion in cancer research focused on targeted cancer therapy.
In acute myeloid leukemia, various mutations in the FMS like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase (RTK), result in rapid proliferation of abnormal immature …show more content…
The first generation of FLT3 inhibitors include midostaurin, soafenib among a number of other drugs. Extensive research has been done on these inhibitors as single agents as well as coupled with chemotherapy, however they have only shown moderate effects [cite the group’s papers]. The modest effects of the first generation drugs can be attributed to the fact that AML is driven by multiple, abnormal signaling pathways while the first generation TKIs simply targeted a single singling pathway. This necessitated the development of more potent inhibitors, such as the second generation FLT3 inhibitors. These include quizartinib, crenolib, among more selective inhibitors. However, although none of the previously discussed FLT3 TKIs have not been approved for sale and clinical use, multiple early clinical trial studies have shown the development of resistant mechanisms. This resistance is defined as a loss of efficacy, and can be attributed to pharmokinetics, receptor-conferring point mutations, as well as activation of prosurvival …show more content…
While TKD2 mutations, such as D835, conferred a higher resistance than TKD1, the combination of a TDK1 and TKD2 mutation offered the greatest resistance to the TKI. Zhang further showed that the presence of a TKD2 mutation corresponded with elevated levels of markers that indicated the upmodulation of MAPK/ERK as well as AKT/S6K signaling pathways. The TKD mutation was also shown to confer a resistance towards the more potent TKI: quizartinib. This was further confirmed in a study conducted by Smith et al7, where the group showed that the presence of a D835 provided a high degree of resistance to quizartinib. They went onto show that the degree of resistance associated with quizartinib was similar to that of
In acute myeloid leukemia, various mutations in the FMS like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase (RTK), result in rapid proliferation of abnormal immature …show more content…
The first generation of FLT3 inhibitors include midostaurin, soafenib among a number of other drugs. Extensive research has been done on these inhibitors as single agents as well as coupled with chemotherapy, however they have only shown moderate effects [cite the group’s papers]. The modest effects of the first generation drugs can be attributed to the fact that AML is driven by multiple, abnormal signaling pathways while the first generation TKIs simply targeted a single singling pathway. This necessitated the development of more potent inhibitors, such as the second generation FLT3 inhibitors. These include quizartinib, crenolib, among more selective inhibitors. However, although none of the previously discussed FLT3 TKIs have not been approved for sale and clinical use, multiple early clinical trial studies have shown the development of resistant mechanisms. This resistance is defined as a loss of efficacy, and can be attributed to pharmokinetics, receptor-conferring point mutations, as well as activation of prosurvival …show more content…
While TKD2 mutations, such as D835, conferred a higher resistance than TKD1, the combination of a TDK1 and TKD2 mutation offered the greatest resistance to the TKI. Zhang further showed that the presence of a TKD2 mutation corresponded with elevated levels of markers that indicated the upmodulation of MAPK/ERK as well as AKT/S6K signaling pathways. The TKD mutation was also shown to confer a resistance towards the more potent TKI: quizartinib. This was further confirmed in a study conducted by Smith et al7, where the group showed that the presence of a D835 provided a high degree of resistance to quizartinib. They went onto show that the degree of resistance associated with quizartinib was similar to that of