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PMID

(20520641)

Authors

von Bubnoff N, Rummelt C, Menzel H, Sigl M, Peschel C, Duyster J

Title

Identification of a secondary FLT3/A848P mutation in a patient with FLT3-ITD-positive blast phase CMML and response to sunitinib and sorafenib.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	24	8	2010 Aug	1523-5	Leukemia

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
FLT3	A848P	missense	gain of function - predicted	FLT3 A848P lies within the protein kinase domain of the Flt3 protein (UniProt.org). A848P results in growth factor independent cell proliferation, Flt3 phosphorylation, and Erk activation in culture (Blood; 2009, 114;22, Abstract #3982), and has been demonstrated to confer resistance to FLT3 inhibitors in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations in culture (PMID: 20520641), and therefore, is predicted to lead to a gain of Flt3 protein function.	Y

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins FLT3 A848P	chronic myelomonocytic leukemia	predicted - resistant	Sorafenib + Sunitinib	Case Reports/Case Series	Actionable	In a clinical case study, FLT3 A848P was identified after progression on the alternating treatment of Nexvar (sorafenib) and Sutent (sunitinib) in a patient with chronic myelomoncytic leukemia harboring a FLT3-ITD mutation (PMID: 20520641).	20520641
FLT3 exon 14 ins FLT3 A848P	hematologic cancer	resistant	Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing FLT3-ITD with FLT3 A848P were resistant to Nexavar (sorafenib) in culture (PMID: 20520641).	20520641
FLT3 exon 14 ins FLT3 A848P	hematologic cancer	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, Rydapt (midostaurin) treatment inhibited growth of cells expressing FLT3-ITD with FLT3 A848P in culture (PMID: 20520641).	20520641
FLT3 exon 14 ins FLT3 A848P	hematologic cancer	resistant	Sunitinib	Preclinical - Cell culture	Actionable	In a preclinical study, cells expressing FLT3-ITD with FLT3 A848P were resistant to Sutent (sunitinib) in culture (PMID: 20520641).	20520641

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