A brand new editorial paper was revealed in Oncotargettitled “Impact of SHP2 tyrosine phosphorylation on the development of acquired resistance to allosteric SHP2 inhibitors.”
The SH2 domain-containing tyrosine phosphatase 2 (SHP2) is a ubiquitously expressed non-receptor protein tyrosine phosphatase, encoded by the PTPN11 gene. It’s positively regulated by upstream receptor tyrosine kinases (RTKs) to activate downstream the RAS-ERK pathway.
On this new editorial, researchers Giulia Franciosa and Jesper V. Olsen from the College of Copenhagen talk about potential leukemia therapies that successfully stop adaptive resistance. Acute myeloid leukemia (AML) is a bone marrow malignancy characterised by a blockage of differentiation and an uncontrolled proliferation of myeloid hematopoietic progenitor cells.
The interior tandem duplication (ITD) within the juxtamembrane area of the RTK FLT3 is an oncogenic driver mutation that results in constitutive activation of its tyrosine kinase exercise. Consequently, FLT3 inhibitors that block its tyrosine kinase exercise symbolize the focused remedy possibility for sufferers with FLT3-ITD AML, usually administrated together with induction chemotherapy.
“Nonetheless, the quick period of remission urges the event of novel combinatorial therapies for FLT3-ITD AML,” the researchers write.
Since 2016, a number of potent and selective allosteric, noncovalent SHP2 inhibitors have been developed and examined in scientific trials for strong tumors. A current research reported the effectiveness of short-term remedy with the allosteric SHP2 inhibitor SHP099 as a single agent in clinically related mouse fashions of Flt3-ITD AML. This remark was in distinction with revealed knowledge exhibiting that allosteric SHP2 inhibition is barely efficient as mixture remedy with inhibitors of different nodes of the RAS-ERK pathway.
In a research article revealed by Pfeiffer et al., the Olsen’s lab at College of Copenhagen confirmed that two industrial FLT3-ITDpositive AML cell strains (MV-4-11 and MOLM-13) developed adaptive resistance after extended remedy in vitro with the allosteric SHP2 inhibitor SHP099.
“All in all, the findings by Pfeiffer et al. counsel that mixed inhibition of SHP2 and mutated RTKs are efficient in stopping adaptive resistance, but additionally spotlight the necessity for improvement of stronger and efficient SHP2 inhibitors and mixture therapies for scientific purposes,” the researchers conclude.
Giulia Franciosa et al, Influence of SHP2 tyrosine phosphorylation on the event of acquired resistance to allosteric SHP2 inhibitors, Oncotarget (2023). DOI: 10.18632/oncotarget.28392
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Editorial: Mixed inhibition of SHP2 and mutated RTKs stop adaptive resistance in leukemia (2023, November 8)
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