PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease

Abstract

FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.

Effects of PKC412, Nilotinib, and Imatinib Against GIST-Associated PDGFRA Mutants With Differential Imatinib Sensitivity

“…PKC412 has previously been shown to be an effective inhibitor of the imatinib-resistant c-KIT mutant, D816V, which is associated with systemic mast cell disease14 , 15. PKC412 has also been shown to be effective against the FIP1L1-PDGFRA kinase associated with hypereosinophilic syndrome and chronic eosinophilic leukemia 16 , and can override imatinib resistance occurring in point mutated FIP1L1-PDGFRA-induced myeloproliferative disease 17 . In addition, GIST patient samples positive for the imatinib resistant mutant c-KIT or PDGFRA were found to respond well to PKC412 8 .…”

Five years since the discovery of FIP1L1–PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias

“…PKC412, a potent FLT3 inhibitor that is in clinical development for the treatment of AML, was the first inhibitor to be identified with activity against the FIP1L1-PDGFRa T674I mutant. 65 Using both in vitro and in vivo mouse models, we demonstrated the ability of PKC412 to induce apoptosis in FIP1L1-PDGFRa T674I-transformed cells, and to significantly reduce leukocytosis and splenomegaly in a FIP1L1-PDGFRa T674I mouse model. 65 In a second study, we identified sorafenib, a BRAF and VEGFR inhibitor approved for the treatment of renal cell carcinoma, as another potent inhibitor of both FIP1L1-PDGFRa and the T674I mutant form.…”

“…65 Using both in vitro and in vivo mouse models, we demonstrated the ability of PKC412 to induce apoptosis in FIP1L1-PDGFRa T674I-transformed cells, and to significantly reduce leukocytosis and splenomegaly in a FIP1L1-PDGFRa T674I mouse model. 65 In a second study, we identified sorafenib, a BRAF and VEGFR inhibitor approved for the treatment of renal cell carcinoma, as another potent inhibitor of both FIP1L1-PDGFRa and the T674I mutant form. 89 In addition, nilotinib was also shown to have some activity towards both FIP1L1-PDGFRa and the T674I mutant.…”

“…The essential role of FIP1L1-PDGFRA is clear from in vitro studies with the EOL-1 cell line, from mouse models of FIP1L1-PDGFRA induced disease, and from the remarkable responses of FIP1L1-PDFGRA-positive CEL patients to imatinib treatment. 8,18,65,66 The mouse model, however, has also suggested that expression of the FIP1L1-PDGFRA fusion is most likely not sufficient to cause eosinophilia, as mice expressing FIP1L1-PDGFRA in their bone marrow cells develop a general myeloproliferative disease without eosinophilia. 65 Expression of FIP1L1-PDGFRA together with overexpression of IL-5, however, mimics the disease much better in the mouse, with typical features of HES such as tissue infiltration of eosinophils.…”

“…8,18,65,66 The mouse model, however, has also suggested that expression of the FIP1L1-PDGFRA fusion is most likely not sufficient to cause eosinophilia, as mice expressing FIP1L1-PDGFRA in their bone marrow cells develop a general myeloproliferative disease without eosinophilia. 65 Expression of FIP1L1-PDGFRA together with overexpression of IL-5, however, mimics the disease much better in the mouse, with typical features of HES such as tissue infiltration of eosinophils. 67 Similarly, a study of polymorphic variation at the IL-5 receptor-a (IL5RA) gene revealed an association between a SNP in the 5 0 UTR of IL5RA and the eosinophil count/presence of tissue infiltration in FIP1L1-PDGFRA-positive HES patients.…”