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Experimental and Molecular Therapeutics

Abstract 19: Identification of a novel mode of kinase inhibitor resistance: An F604S exchange in FIP1L1-PDGFRA modulates FIP1L1-PDGFRA protein stability in a SHP-2 and SRC-dependent manner

Gorantla P. Sivahari, Nikolas Von Bubnoff, Ana Lena Illert, Nicolas Schneider, Christian Peschel and Justus Duyster
Gorantla P. Sivahari
1Technical University of Munich, Munich, Germany.
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Nikolas Von Bubnoff
1Technical University of Munich, Munich, Germany.
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Ana Lena Illert
1Technical University of Munich, Munich, Germany.
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Nicolas Schneider
1Technical University of Munich, Munich, Germany.
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Christian Peschel
1Technical University of Munich, Munich, Germany.
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Justus Duyster
1Technical University of Munich, Munich, Germany.
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DOI: 10.1158/1538-7445.AM10-19 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

FIP1L1-PDGFR alpha is a constitutively activated protein kinase which was reported in chronic eosinophilic leukemia (CEL) and in cases of hypereosinophilic syndrome and mastocytosis with eosinophilia. Imatinib is clinically active against FIP1L1-PDGFRA positive disease. However, clinical resistance to imatinib has been observed in FIP1L1-PDGFRA positive leukemia and was shown to occur due to a secondary mutation (T674I) in the PDGFR alpha kinase domain. Using a screening strategy to identify imatinib resistant mutations, we generated numerous imatinib resistant cell clones. Analysis of the PDGFRA kinase domain in these cell clones revealed a broad spectrum of resistance mutations including the clinically reported exchange T674I. Interestingly, one of the abundant mutations was a Phe to Ser exchange at position 604 (F604S), which occurred alone or in combination with other exchanges. Surprisingly, FIP1L1-PDGFRA/F604S in contrast to D842H and F604+D842H did not increase the biochemical or cellular IC50 value to imatinib when compared to wild-type (wt). However, F604S and F604S+D842H transformed Ba/F3, NIH3T3 and mouse bone marrow more efficiently compared to wt and D842H, respectively. Immunoprecipitation and immunoblotting indicated increased amounts of FIP1L1-PDGFRA protein in F604S versus wt cells. Pulse chase analysis revealed that FIP1L1-PDGFRA/F604S is strongly stabilised compared to wt. SRC coimmunoprecipitated with FIP1L1-PDGFRA in wt, but not F604S cells. Co-expression of SRC in 293T cells augmented degradation of wt, but not F604S FIP1L1-PDGFRA, indicating that SRC is a negative regulator of FIP1L1-PDGFRA protein stability. Importantly both, the SRC inhibitor PD166326 and SRC siRNA mimicked the F604S phenotype and resulted in stabilization of the wt protein. Importantly, phosphatase inhibitor treatment of FIP1L1-PDGFRA/F604S led to destabilization and SRC recruitment indicating that phosphatases might be responsible for the enhanced stability of FIP1L1-PDGFRA/F604S. In fact, coimmunuprecipitaion experiments identified the phosphatase SHP2 as a specific binding partner of F604S mutated FP. Together, these results suggest that stabilization of FIP1L1-PDGFRA/F604S is due to dephosphorylation by SHP-2 leading to lesser activation of the SRC and Cbl mediated ubiquitination machinery. In summary, imatinib resistance screening identified a novel class of resistance mutations in FIP1L1-PDGFRA, that do not act by impeding drug binding to the target, but increased target stability and abundance by interfering with SRC- mediated degradation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 19.

  • ©2010 American Association for Cancer Research
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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract 19: Identification of a novel mode of kinase inhibitor resistance: An F604S exchange in FIP1L1-PDGFRA modulates FIP1L1-PDGFRA protein stability in a SHP-2 and SRC-dependent manner
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Abstract 19: Identification of a novel mode of kinase inhibitor resistance: An F604S exchange in FIP1L1-PDGFRA modulates FIP1L1-PDGFRA protein stability in a SHP-2 and SRC-dependent manner
Gorantla P. Sivahari, Nikolas Von Bubnoff, Ana Lena Illert, Nicolas Schneider, Christian Peschel and Justus Duyster
Cancer Res April 15 2010 (70) (8 Supplement) 19; DOI: 10.1158/1538-7445.AM10-19

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Abstract 19: Identification of a novel mode of kinase inhibitor resistance: An F604S exchange in FIP1L1-PDGFRA modulates FIP1L1-PDGFRA protein stability in a SHP-2 and SRC-dependent manner
Gorantla P. Sivahari, Nikolas Von Bubnoff, Ana Lena Illert, Nicolas Schneider, Christian Peschel and Justus Duyster
Cancer Res April 15 2010 (70) (8 Supplement) 19; DOI: 10.1158/1538-7445.AM10-19
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