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

Weisberg, Ellen; Wright, Renee D.; Jiang, Jingrui; Ray, Arghya; Moreno, Daisy; Manley, Paul W.; Fabbro, Doriano; Hall-Meyers, Elizabeth; Catley, Laurie; Podar, Klaus; Kung, Andrew L.; Griffin, James D.

doi:10.1053/j.gastro.2006.09.017

Cited by 90 publications

(43 citation statements)

References 21 publications

(22 reference statements)

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“…We recovered FP/D842V with nilotinib and sorafenib, but missed this exchange with imatinib, although three other exchanges at the same position emerged with imatinib (D842E/G/H). In full-length PDGFRA, the D842V exchange was shown to cause resistance to nilotinib (Weisberg et al, 2006), whereas PKC412, sorafenib and dasatinib had some residual activity, although at concentrations that might be above achievable plasma levels (Debiec-Rychter et al, 2005;Guida et al, 2007;Dewaele et al, 2008). However, in FP, D842V does not respond to imatinib, nilotinib, sorafenib and dasatinib at clinically achievable levels (this work and Lierman et al, 2009).…”

Section: Discussionmentioning

confidence: 76%

The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro

et al. 2010

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Myeloproliferation with prominent eosinophilia is associated with rearrangements of PDGFR-A or -B. The most common rearrangement is FIP1L1-PDGFRA (FP). The majority of patients with PDGFR-rearranged myeloproliferation respond to treatment with imatinib. In contrast to BCR-ABL-positive chronic myelogenous leukemia, only few cases of imatinib resistance and mutations of the FP kinase domain have been described so far. We hypothesized that the number of critical residues mediating imatinib resistance in FP in contrast to BCR-ABL might be limited. We performed an established systematic and comprehensive in vitro resistance screen to determine the pattern and frequency of possible TKI resistance mutations in FP. We identified 27 different FP kinase domain mutations including 25 novel variants, which attenuated response to imatinib, nilotinib or sorafenib. However, the majority of these exchanges did not confer complete inhibitor resistance. At clinically achievable drug concentrations, FP/ T674I predominated with imatinib, whereas with nilotinib and sorafenib, FP/D842V and the compound mutation T674I þ T874I became prevalent. Our results suggest that the PDGFR kinase domain contains a limited number of residues where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations, which might explain the low frequency of imatinib resistance in this patient population. In addition, these findings would help to select the appropriate second-line drug in cases of imatinib-resistant disease and may be translated to other neoplasms driven by activated forms of PDGFR-A or -B.

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Section: Discussionmentioning

confidence: 76%

The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro

et al. 2010

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“…112 On the basis of in vitro data, the most common PDGFRA mutation in GISTs, D842V, is fully resistant to the effects of imatinib. 34,38,127,128 This mutation favors the active conformation of the kinase domain and consequently disfavors imatinib binding. 34,129,130 This is corroborated by clinical results, as patients with PDGFRA D842V-mutant GIST have low response rates and very short progression-free and overall survivals during imatinib treatment.…”

Section: Primary Resistancementioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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“…These substitutions are postulated to destabilize the inactive conformation required for efficient binding by type II TKIs such as quizartinib. Analogous substitutions in KIT (KIT/D816V) and platelet-derived growth factor receptor (PDGFR) (PDGFR/ D842V) confer a high degree of resistance to type II TKIs (13,14). Although a number of potent second-generation type II FLT3 TKIs are currently undergoing clinical development for the treatment of AML and/or have reported single agent activity (e.g., sorafenib) (15), these agents, including the pan-BCR-ABL inhibitor ponatinib, which has potent activity against FLT3, are uniformly ineffective at inhibiting quizartinib-resistant FLT3-ITD/D835 mutants (12,16).…”

mentioning

confidence: 99%

Crenolanib is a selective type I pan-FLT3 inhibitor

Smith

Lasater²,

Lin³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

188

148

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Tyrosine kinase inhibitors (TKIs) represent transformative therapies for several malignancies. Two critical features necessary for maximizing TKI tolerability and response duration are kinase selectivity and invulnerability to resistance-conferring kinase domain (KD) mutations in the intended target. No prior TKI has demonstrated both of these properties. Aiming to maximize selectivity, medicinal chemists have largely sought to create TKIs that bind to an inactive (type II) kinase conformation. Here we demonstrate that the investigational type I TKI crenolanib is a potent inhibitor of Fms tyrosine kinase-3 (FLT3) internal tandem duplication, a validated therapeutic target in human acute myeloid leukemia (AML), as well as all secondary KD mutants previously shown to confer resistance to the first highly active FLT3 TKI quizartinib. Moreover, crenolanib is highly selective for FLT3 relative to the closely related protein tyrosine kinase KIT, demonstrating that simultaneous FLT3/KIT inhibition, a prominent feature of other clinically active FLT3 TKIs, is not required for AML cell cytotoxicity in vitro and may contribute to undesirable toxicity in patients. A saturation mutagenesis screen of FLT3-internal tandem duplication failed to recover any resistant colonies in the presence of a crenolanib concentration well below what has been safely achieved in humans, suggesting that crenolanib has the potential to suppress KD mutation-mediated clinical resistance. Crenolanib represents the first TKI to exhibit both kinase selectivity and invulnerability to resistance-conferring KD mutations, which is unexpected of a type I inhibitor. Crenolanib has significant promise for achieving deep and durable responses in FLT3-mutant AML, and may have a profound impact upon future medicinal chemistry efforts in oncology.sorafenib | activation-loop mutations | D835 mutations P ioneering studies demonstrated that imatinib, the first small molecule tyrosine kinase inhibitor (TKI), binds to an inactive kinase conformation of the Abelson protein tyrosine kinase (ABL) (1). Compounds that bind to kinases in this manner have been termed "type II", whereas "type I" inhibitors bind to an active conformation. Type II inhibitors typically target the ATP binding region and an adjacent allosteric site available only in an inactive conformation. Because this region is less well conserved among kinases than the ATP binding region, interactions with this area allow for greater selectivity.Despite the clinical success of imatinib for the treatment of chronic myeloid leukemia (CML), durability of response is compromised by secondary kinase domain (KD) mutations in BCR-ABL (1), many of which destabilize the inactive conformation required for imatinib binding (1). Second-generation ABL inhibitors, dasatinib (type I) and nilotinib (type II), were subsequently developed to retain efficacy against most imatinib-resistant BCR-ABL KD mutants, and each are vulnerable to only approximately five resistance-conferring mutations (2, 3). In contrast, the third-gene...

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

Cited by 90 publications

References 21 publications

The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro

The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro

Gastrointestinal stromal tumors: what do we know now?

Crenolanib is a selective type I pan-FLT3 inhibitor

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