The ABL Switch Control Inhibitor DCC-2036 Is Active against the Chronic Myeloid Leukemia Mutant BCR-ABLT315I and Exhibits a Narrow Resistance Profile

Eide, Christopher A.; Adrian, Lauren T.; Tyner, Jeffrey W.; Partlin, Mary Mac; Anderson, David J.; Wise, Scott; Smith, Bryan D.; Petillo, Peter A.; Flynn, Daniel L.; Deininger, Michael W.; O’Hare, Thomas; Druker, Brian J.

doi:10.1158/0008-5472.can-10-3224

Cited by 89 publications

(71 citation statements)

References 21 publications

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“…A new class of non-ATP mimetic kinase inhibitors (switch pocket kinase inhibitors, such as DP-2976) have shown high potency when tested in vitro and represent hope in the fight against TKI resistance. 148,149 Summary and future directions Achievements in the treatment of GISTs during the past decade are the direct result of a growing understanding of their molecular biology. The high frequency of primary KIT and PDGFRA mutations in these tumors makes them sensitive to kinase inhibitors such as imatinib, and this drug is FDAapproved for use in both the adjuvant and advanced disease settings.…”

Section: Approaches To Imatinib-resistant Gistmentioning

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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Section: Approaches To Imatinib-resistant Gistmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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“…For the T315I mutant inhibitors including ponatinib (AP24534), a pan BCR-ABL inhibitor (Phase II) and DCC-2036, a "switch-control" inhibitor (Phase I), have advanced to clinical trials. [34][35][36][37] Combination studies: In an effort to make patients' responses more robust, clinical trials have been launched involving the use of TKIs in combination with other drugs that could potentially augment TKI-induced cell death. One such study combines imatinib with peginterferon alfa-2a or cytarabine and currently shows a significant advantage for the interferon combination in terms of molecular responses (overall survival and progression free survival unchanged).…”

Section: The Problem Of Resistancementioning

confidence: 99%

Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML

Helgason

Karvela

Holyoake

2011

Blood

109

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The introduction of imatinib in the treatment of chronic myeloid leukaemia (CML) represents the most successful example of targeted therapy in human cancer. However, leukaemic stem cells (LSCs) are insensitive to tyrosine kinase inhibitors (TKIs) and contribute to disease persistence by representing a reservoir of selfrenewing cells that replenish the disease upon drug discontinuation. This has refocused the interest of scientists towards drug combinations i.e. treating with TKIs and simultaneously targeting alternative survival mechanisms. One candidate target mechanism is autophagy, a cellular recycling process that acts as a cytoprotective shield in CML cells in response to TKI-induced stress and in other cancer cells surviving in an inhospitable microenvironment. On that basis, inhibition of autophagy has now become an exciting option for combination treatment in cancer and clinical trials have been initiated in solid and haemopoietic tumours such as CML, chronic lymphocytic leukaemia (CLL) and multiple myeloma. This review describes the biology of CML and elucidates how the molecular driver BCR-ABL led to the development of TKIs. We then discuss the molecular regulation of autophagy and the potential for autophagy inhibition as the next step in our attempt to tackle the problem of CML persistence to offer a curative option.

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“…Most BCR-ABL mutants are susceptible to alternative ABL tyrosine kinase inhibitor (TKI) therapies. [3][4][5][6][7][8] Sequencing of the BCR-ABL kinase domain in patients exhibiting signs of TKI treatment failure has also revealed the presence of alternatively spliced variants, including BCR-ABL 35INS , in which retention of 35 intronic nucleotides at the exon 8/9 splice junction introduces a stop codon after 10 intron-encoded residues. [9][10][11][12][13] The result is loss of the last 653 residues of BCR-ABL, including 22 native kinase domain residues.…”

Section: Introductionmentioning

confidence: 99%

The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia

O’Hare

Zabriskie

Eide

et al. 2011

Blood

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Chronic myeloid leukemia is effectively treated with imatinib, but reactivation of BCR-ABL frequently occurs through acquisition of kinase domain mutations. The additional approved ABL tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib, along with investigational TKIs such as ponatinib (AP24534) and DCC-2036, support the possibility that mutationmediated resistance in chronic myeloid leukemia can be fully controlled; however, the molecular events underlying resistance in patients lacking BCR-ABL point mutations are largely unknown. We previously reported on an insertion/ truncation mutant, BCR-ABL 35INS IntroductionImatinib is an inhibitor of BCR-ABL, the tyrosine kinase that causes chronic myeloid leukemia (CML). Most newly diagnosed patients achieve durable remissions on imatinib therapy, 1,2 but 10%-15% fail to respond or relapse. The leading cause of imatinib resistance is reactivation of BCR-ABL because of kinase domain point mutations. Most BCR-ABL mutants are susceptible to alternative ABL tyrosine kinase inhibitor (TKI) therapies. [3][4][5][6][7][8] Sequencing of the BCR-ABL kinase domain in patients exhibiting signs of TKI treatment failure has also revealed the presence of alternatively spliced variants, including BCR-ABL 35INS , in which retention of 35 intronic nucleotides at the exon 8/9 splice junction introduces a stop codon after 10 intron-encoded residues. 9-13 The result is loss of the last 653 residues of BCR-ABL, including 22 native kinase domain residues. 10,12 Notably, the reported frequency of detection of the BCR-ABL 35INS mutant in cases of imatinib resistance (including instances in which a point mutation is concurrently detected in the BCR-ABL kinase domain) as detected by direct sequencing is ϳ1%-2%, 10,14 although more sensitive quantitative assays have reported detection of very low levels of the mutant transcript at a considerably increased prevalence. 14 Although BCR-ABL truncated immediately after the ABL kinase domain is fully transforming in a murine model of CML, 15 we predicted BCR-ABL 35INS would lack kinase activity, because the mutation eliminates the last 2 helices of the ABL kinase domain and disrupts a complex set of interactions among noncontiguous residues. 10 By contrast, recent reports have suggested that BCR-ABL 35INS confers TKI resistance in CML 9,12,14,16 and have proposed a BCR-ABL 35INS tailored clinical trial, 16 but they have not addressed the mechanism for this or assessed BCR-ABL 35INS catalytic activity. We provide cell-based and biochemical studies of BCR-ABL 35INS and a retrospective analysis of its detection in the context of treatment and response in CML patients. Methods IL-3 withdrawalBa/F3 cells cultured in standard media (RPMI 1640 media, 10% FBS, L-glutamine, penicillin-streptomycin; Invitrogen) containing IL-3 from WEHI-conditioned media were infected with retrovirus expressing BCR-ABL, BCR-ABL 35INS , or BCR-ABL K271P/35INS (MSCV-IRES-GFP), and stable cell lines were sorted for GFP (FACSAria II; BD Biosciences). (E) Equimolar amounts...

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The ABL Switch Control Inhibitor DCC-2036 Is Active against the Chronic Myeloid Leukemia Mutant BCR-ABLT315I and Exhibits a Narrow Resistance Profile

Cited by 89 publications

References 21 publications

Gastrointestinal stromal tumors: what do we know now?

Gastrointestinal stromal tumors: what do we know now?

Kill one bird with two stones: potential efficacy of BCR-ABL and autophagy inhibition in CML

The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia

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