proto oncogene proteins c abl


Summary: Non-receptor tyrosine kinases encoded by the C-ABL GENES. They are distributed in both the cytoplasm and the nucleus. c-Abl plays a role in normal HEMATOPOIESIS especially of the myeloid lineage. Oncogenic transformation of c-abl arises when specific N-terminal amino acids are deleted, releasing the kinase from negative regulation.

Top Publications

  1. Okram B, Nagle A, Adrian F, Lee C, Ren P, Wang X, et al. A general strategy for creating "inactive-conformation" abl inhibitors. Chem Biol. 2006;13:779-86 pubmed
    ..We demonstrate that the designed compounds function as type II inhibitors by using biochemical and cellular kinase assays and by cocrystallography with Abl. ..
  2. Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007;25:1035-44 pubmed
    ..The data suggest that our approach is a valuable tool for drug discovery. ..
  3. Srinivasan D, Sims J, Plattner R. Aggressive breast cancer cells are dependent on activated Abl kinases for proliferation, anchorage-independent growth and survival. Oncogene. 2008;27:1095-105 pubmed
    ..Since activation of Abl kinases affects multiple steps of breast cancer development and progression, Abl kinase inhibitors are likely to be effective agents for the treatment of breast cancers containing highly active Abl kinases. ..
  4. Radha V, Rajanna A, Mitra A, Rangaraj N, Swarup G. C3G is required for c-Abl-induced filopodia and its overexpression promotes filopodia formation. Exp Cell Res. 2007;313:2476-92 pubmed
    ..We suggest that C3G and c-Abl function in an interdependent manner, in linking external signals to remodeling the cytoskeleton to induce filopodia. ..
  5. Burton E, Plattner R, Pendergast A. Abl tyrosine kinases are required for infection by Shigella flexneri. EMBO J. 2003;22:5471-9 pubmed
    ..Together, these findings reveal a new role for the Abl kinases, and suggest a novel approach to treatment of Shigella infections through inhibition of host cell signaling pathways. ..
  6. Li B, Wang X, Rasheed N, Hu Y, Boast S, Ishii T, et al. Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C delta. Genes Dev. 2004;18:1824-37 pubmed
    ..Hence, our results unveiled a previously unrecognized mechanism by which c-Abl and Atm participate in oxidative stress response. ..
  7. Hantschel O, Wiesner S, Guttler T, Mackereth C, Rix L, Mikes Z, et al. Structural basis for the cytoskeletal association of Bcr-Abl/c-Abl. Mol Cell. 2005;19:461-73 pubmed
    ..We propose that these interactions represent a major determinant for both Bcr-Abl and c-Abl localization. ..
  8. Kain K, Gooch S, Klemke R. Cytoplasmic c-Abl provides a molecular 'Rheostat' controlling carcinoma cell survival and invasion. Oncogene. 2003;22:6071-80 pubmed
    ..Together, these data illustrate that c-Abl prevents aberrant motility and survival through Crk 221 phosphorylation and modulation of Crk/CAS complexes, and that deregulation of this pathway contributes to cell metastasis. ..
  9. O Hare T, Walters D, Stoffregen E, Sherbenou D, Heinrich M, Deininger M, et al. Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. Clin Cancer Res. 2005;11:6987-93 pubmed
    ..Our results indicate that Src/Abl inhibitors are compatible with imatinib and suggest that combined Abl inhibitor therapy is a feasible treatment strategy for patients with CML. ..

More Information


  1. Hernandez S, Krishnaswami M, Miller A, Koleske A. How do Abl family kinases regulate cell shape and movement?. Trends Cell Biol. 2004;14:36-44 pubmed
    ..Emerging evidence suggests that Abl family kinases can use these domains to directly organize cytoskeletal structure in vivo. ..
  2. Jin H, Wang J. Abl tyrosine kinase promotes dorsal ruffles but restrains lamellipodia extension during cell spreading on fibronectin. Mol Biol Cell. 2007;18:4143-54 pubmed
    ..The Abl-dependent dorsal membrane localization of activated Rac explains its positive role in ruffling and negative role in cell spreading and migration. ..
  3. Swimm A, Bommarius B, Li Y, Cheng D, Reeves P, Sherman M, et al. Enteropathogenic Escherichia coli use redundant tyrosine kinases to form actin pedestals. Mol Biol Cell. 2004;15:3520-9 pubmed
    ..Our results raise the possibility that PD may be useful in treating EPEC infections, and because PD affects host and not bacterium, selecting resistant strains may be far less likely than with conventional antibiotics. ..
  4. Leng Y, Zhang J, Badour K, Arpaia E, Freeman S, Cheung P, et al. Abelson-interactor-1 promotes WAVE2 membrane translocation and Abelson-mediated tyrosine phosphorylation required for WAVE2 activation. Proc Natl Acad Sci U S A. 2005;102:1098-103 pubmed
    ..Together, these data reveal that Abi-1-mediated coupling of Abl to WAVE2 promotes Abl-evoked WAVE2 tyrosine phosphorylation required to link WAVE2 with activated Rac and with actin polymerization and remodeling at the cell periphery. ..
  5. Daniels C, Wilkes M, Edens M, Kottom T, Murphy S, Limper A, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest. 2004;114:1308-16 pubmed
    ..Thus, Abl family members represent common targets for the modulation of profibrotic cytokine signaling. ..
  6. Preyer M, Shu C, Wang J. Delayed activation of Bax by DNA damage in embryonic stem cells with knock-in mutations of the Abl nuclear localization signals. Cell Death Differ. 2007;14:1139-48 pubmed
    ..These results provide a genetic proof that Abl nuclear entry contributes to DNA damage-induced activation of the intrinsic apoptotic pathway. ..
  7. Master Z, Tran J, Bishnoi A, Chen S, Ebos J, Van Slyke P, et al. Dok-R binds c-Abl and regulates Abl kinase activity and mediates cytoskeletal reorganization. J Biol Chem. 2003;278:30170-9 pubmed
    ..Our data are the first to demonstrate that Dok-R and c-Abl interact in both a constitutive and inducible fashion and that Dok-R influences the intracellular kinase and biological activity of c-Abl. ..
  8. Young M, Shah N, Chao L, Seeliger M, Milanov Z, Biggs W, et al. Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res. 2006;66:1007-14 pubmed
  9. Levinson N, Kuchment O, Shen K, Young M, Koldobskiy M, Karplus M, et al. A Src-like inactive conformation in the abl tyrosine kinase domain. PLoS Biol. 2006;4:e144 pubmed
    ..Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain. ..
  10. Tokarski J, Newitt J, Chang C, Cheng J, Wittekind M, Kiefer S, et al. The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 2006;66:5790-7 pubmed
    ..The structure also provides an explanation for the activity of dasatinib against imatinib-resistant BCR-ABL mutants. ..
  11. Noren N, Foos G, Hauser C, Pasquale E. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nat Cell Biol. 2006;8:815-25 pubmed
    ..These findings identify a novel Eph receptor signalling pathway with tumour-suppressor activity and predict that therapeutic intervention to activate EphB4 signalling will inhibit tumour progression. ..
  12. Conilleau S, Takizawa Y, Tachiwana H, Fleury F, Kurumizaka H, Takahashi M. Location of tyrosine 315, a target for phosphorylation by cAbl tyrosine kinase, at the edge of the subunit-subunit interface of the human Rad51 filament. J Mol Biol. 2004;339:797-804 pubmed
    ..Correct prediction of subunit-subunit interface of Rad51 by simple comparison of structures of Rad51 and RecA supports the idea that Rad51 forms the filament in a similar way as does RecA. ..
  13. Zandy N, Pendergast A. Abl tyrosine kinases modulate cadherin-dependent adhesion upstream and downstream of Rho family GTPases. Cell Cycle. 2008;7:444-8 pubmed
  14. Iacob R, Pene Dumitrescu T, Zhang J, Gray N, Smithgall T, Engen J. Conformational disturbance in Abl kinase upon mutation and deregulation. Proc Natl Acad Sci U S A. 2009;106:1386-91 pubmed publisher
    ..Similar analyses could be performed on any protein to provide mechanistic details about conformational changes and protein function. ..
  15. Modugno M, Casale E, Soncini C, Rosettani P, Colombo R, Lupi R, et al. Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358. Cancer Res. 2007;67:7987-90 pubmed
  16. Jones S, Lu H, Lu Q. Abl tyrosine kinase promotes dendrogenesis by inducing actin cytoskeletal rearrangements in cooperation with Rho family small GTPases in hippocampal neurons. J Neurosci. 2004;24:8510-21 pubmed
    ..Together, these studies support a critical role for Abl kinases in regulating dendrogenesis by inducing actin cytoskeletal rearrangements in cooperation with Rho GTPases. ..
  17. Backert S, Feller S, Wessler S. Emerging roles of Abl family tyrosine kinases in microbial pathogenesis. Trends Biochem Sci. 2008;33:80-90 pubmed publisher
    ..Therapeutic intervention against Abl kinase activity might be an effective and novel strategy to combat serious microbial diseases. ..
  18. Huang Y, Comiskey E, Dupree R, Li S, Koleske A, Burkhardt J. The c-Abl tyrosine kinase regulates actin remodeling at the immune synapse. Blood. 2008;112:111-9 pubmed publisher
    ..In addition, c-Abl is required for normal localization of WAVE2 to the immune synapse (IS). These studies identify c-Abl as a key player in the signaling cascade, leading to actin reorganization during T-cell activation. ..
  19. Seeliger M, Ranjitkar P, Kasap C, Shan Y, Shaw D, Shah N, et al. Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations. Cancer Res. 2009;69:2384-92 pubmed publisher
    ..Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile "gatekeeper" mutation, but do not suppress the growth of parental Ba/F3 cells. ..
  20. Filippakopoulos P, Kofler M, Hantschel O, Gish G, Grebien F, Salah E, et al. Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation. Cell. 2008;134:793-803 pubmed publisher
    ..Thus, the SH2 and catalytic domains of active Fes and Abl pro-oncogenic kinases form integrated structures essential for effective tyrosine kinase signaling. ..
  21. Hägerkvist R, Mokhtari D, Lindholm C, Farnebo F, Mostoslavsky G, Mulligan R, et al. Consequences of Shb and c-Abl interactions for cell death in response to various stress stimuli. Exp Cell Res. 2007;313:284-91 pubmed
    ..The findings are in agreement with the notion of Shb playing a pivotal role in modulating c-Abl pro-apoptotic signaling in response to various stress stimuli. ..
  22. Cheng W, Von Kobbe C, Opresko P, Fields K, Ren J, Kufe D, et al. Werner syndrome protein phosphorylation by abl tyrosine kinase regulates its activity and distribution. Mol Cell Biol. 2003;23:6385-95 pubmed
    ..These findings suggest a novel signaling pathway by which c-Abl mediates WRN nuclear localization and catalytic activities in response to DNA damage. ..
  23. Wang J. Controlling Abl: auto-inhibition and co-inhibition?. Nat Cell Biol. 2004;6:3-7 pubmed
    ..The implication of co-inhibition on Abl function is discussed. ..
  24. Wilkes M, Leof E. Transforming growth factor beta activation of c-Abl is independent of receptor internalization and regulated by phosphatidylinositol 3-kinase and PAK2 in mesenchymal cultures. J Biol Chem. 2006;281:27846-54 pubmed
  25. Chen S, Brier S, Smithgall T, Engen J. The Abl SH2-kinase linker naturally adopts a conformation competent for SH3 domain binding. Protein Sci. 2007;16:572-81 pubmed
  26. O Hare T, Druker B. BIRB-796 is not an effective ABL(T315I) inhibitor. Nat Biotechnol. 2005;23:1209-10; author reply 1210-1 pubmed
  27. Azam M, Seeliger M, Gray N, Kuriyan J, Daley G. Activation of tyrosine kinases by mutation of the gatekeeper threonine. Nat Struct Mol Biol. 2008;15:1109-18 pubmed publisher
    ..These results demonstrate that mutation of the gatekeeper threonine is a common mechanism of activation for tyrosine kinases and provide structural insights to guide the development of next-generation inhibitors. ..
  28. Reeves P, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, et al. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med. 2005;11:731-9 pubmed
  29. Palencia A, Cobos E, Mateo P, Martinez J, Luque I. Thermodynamic dissection of the binding energetics of proline-rich peptides to the Abl-SH3 domain: implications for rational ligand design. J Mol Biol. 2004;336:527-37 pubmed
    ..The implications of these results for rational ligand design are discussed. ..
  30. Zhou T, Parillon L, Li F, Wang Y, Keats J, Lamore S, et al. Crystal structure of the T315I mutant of AbI kinase. Chem Biol Drug Des. 2007;70:171-81 pubmed
    ..The data presented here may provide structural guidance for the design of clinically useful inhibitors of Bcr-AbI T315I. ..
  31. Shan Y, Seeliger M, Eastwood M, Frank F, Xu H, Jensen M, et al. A conserved protonation-dependent switch controls drug binding in the Abl kinase. Proc Natl Acad Sci U S A. 2009;106:139-44 pubmed publisher
  32. Zandy N, Playford M, Pendergast A. Abl tyrosine kinases regulate cell-cell adhesion through Rho GTPases. Proc Natl Acad Sci U S A. 2007;104:17686-91 pubmed
  33. Bradley W, Koleske A. Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts. J Cell Sci. 2009;122:3441-54 pubmed publisher
    ..Elucidating how Abl-family kinases are regulated, and where and when they coordinate cytoskeletal changes, is essential for garnering a better understanding of these complex processes. ..
  34. Hantschel O, Superti Furga G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5:33-44 pubmed
    ..Its oncogenic counterpart, the Bcr-Abl fusion protein, causes certain human leukaemias. Recent insights into the structure and regulation of the c-Abl and Bcr-Abl tyrosine kinases have changed the way we look at these enzymes. ..
  35. Deng X, Hofmann E, Villanueva A, Hobert O, Capodieci P, Veach D, et al. Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation. Nat Genet. 2004;36:906-12 pubmed
    ..These studies indicate that ABL-1 distinguishes proapoptotic signals triggered by two different DNA-damaging agents and suggest that C. elegans might provide tissue models for development of anticancer drugs. ..
  36. Mitsushima M, Takahashi H, Shishido T, Ueda K, Kioka N. Abl kinase interacts with and phosphorylates vinexin. FEBS Lett. 2006;580:4288-95 pubmed
    ..A mutational analysis identified tyrosine 127 on vinexin alpha as a major site of phosphorylation by c- or v-Abl. These results suggest that vinexin alpha is a novel substrate for Abl. ..
  37. Yu D, Khan E, Khaleque M, Lee J, Laco G, Kohlhagen G, et al. Phosphorylation of DNA topoisomerase I by the c-Abl tyrosine kinase confers camptothecin sensitivity. J Biol Chem. 2004;279:51851-61 pubmed
    ..These findings collectively support a model in which c-Abl-mediated phosphorylation of topo I is functionally important to topo I activity and sensitivity to topo I poisons. ..
  38. Harbott L, Nobes C. A key role for Abl family kinases in EphA receptor-mediated growth cone collapse. Mol Cell Neurosci. 2005;30:1-11 pubmed
    ..These results comprise the first evidence that Abl family kinases play a role in EphA receptor-mediated axon guidance. ..
  39. Truong T, Sun G, Doorly M, Wang J, Schwartz M. Modulation of DNA damage-induced apoptosis by cell adhesion is independently mediated by p53 and c-Abl. Proc Natl Acad Sci U S A. 2003;100:10281-6 pubmed
    ..These data suggest that killing of p53-negative tumor cells by chemotherapy would be enhanced by integrin ligation to activate the alternative c-Abl/p73 pathway. ..
  40. Maruoka M, Suzuki J, Kawata S, Yoshida K, Hirao N, Sato S, et al. Identification of B cell adaptor for PI3-kinase (BCAP) as an Abl interactor 1-regulated substrate of Abl kinases. FEBS Lett. 2005;579:2986-90 pubmed
    ..These results show that Abi-1 promotes Abl-mediated BCAP phosphorylation and suggest that Abi-1 in general coordinates kinase-substrate interactions. ..
  41. Vajpai N, Strauss A, Fendrich G, Cowan Jacob S, Manley P, Grzesiek S, et al. Solution conformations and dynamics of ABL kinase-inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib. J Biol Chem. 2008;283:18292-302 pubmed publisher
    ..Nanosecond as well as microsecond dynamics can be detected for certain residues in the activation loop in the inactive and active conformation complexes. ..
  42. Woodring P, Meisenhelder J, Johnson S, Zhou G, Field J, Shah K, et al. c-Abl phosphorylates Dok1 to promote filopodia during cell spreading. J Cell Biol. 2004;165:493-503 pubmed
    ..Our data suggest a novel pathway by which c-Abl transduces signals to the actin cytoskeleton through phosphorylating Dok1 Y361 and recruiting Nck. ..
  43. Gu J, Zhang N, He Y, Koleske A, Pendergast A. Defective T cell development and function in the absence of Abelson kinases. J Immunol. 2007;179:7334-43 pubmed
    ..Together these findings reveal cell-autonomous roles for the Abl family kinases in both T cell development and mature T cell function, and show that loss of these kinases specifically in T cells results in compromised immunity. ..
  44. Grevengoed E, Fox D, Gates J, Peifer M. Balancing different types of actin polymerization at distinct sites: roles for Abelson kinase and Enabled. J Cell Biol. 2003;163:1267-79 pubmed
    ..We also examined other actin regulators. Loss of Abl leads to changes in the localization of the Arp2/3 complex and the formin Diaphanous, and mutations in diaphanous or capping protein beta enhance abl phenotypes. ..
  45. Karplus M, Kuriyan J. Molecular dynamics and protein function. Proc Natl Acad Sci U S A. 2005;102:6679-85 pubmed
    ..We also describe results for the F(1) ATPase molecular motor and the Src family of signaling proteins as examples of applications of simulations to specific biological systems. ..
  46. Burton E, Oliver T, Pendergast A. Abl kinases regulate actin comet tail elongation via an N-WASP-dependent pathway. Mol Cell Biol. 2005;25:8834-43 pubmed
    ..These data demonstrate for the first time that the Abl kinases play a role in the intracellular motility and intercellular dissemination of Shigella and uncover a new role for Abl kinases in the regulation of pathogen motility. ..
  47. Seeliger M, Nagar B, Frank F, Cao X, Henderson M, Kuriyan J. c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty. Structure. 2007;15:299-311 pubmed
    ..Two mutations that are expected to destabilize the inactive Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the free-energy balance between different inactive states is a key to imatinib binding. ..
  48. Cao C, Leng Y, Huang W, Liu X, Kufe D. Glutathione peroxidase 1 is regulated by the c-Abl and Arg tyrosine kinases. J Biol Chem. 2003;278:39609-14 pubmed
    ..Our findings provide the first evidence that GPx1 is regulated by a signaling pathway that is activated in the oxidative stress response. ..
  49. Cao C, Leng Y, Kufe D. Catalase activity is regulated by c-Abl and Arg in the oxidative stress response. J Biol Chem. 2003;278:29667-75 pubmed
    ..These findings indicate that c-Abl and Arg regulate catalase and that this signaling pathway is of importance to apoptosis in the oxidative stress response. ..
  50. Nagar B, Hantschel O, Seeliger M, Davies J, Weis W, Superti Furga G, et al. Organization of the SH3-SH2 unit in active and inactive forms of the c-Abl tyrosine kinase. Mol Cell. 2006;21:787-98 pubmed
    ..This alternative conformation of Abl is likely to prolong the active state of the kinase by preventing it from returning to the autoinhibited state. ..
  51. Woodring P, Hunter T, Wang J. Regulation of F-actin-dependent processes by the Abl family of tyrosine kinases. J Cell Sci. 2003;116:2613-26 pubmed
    ..The modular structure and the nuclear-cytoplasmic shuttling of c-Abl suggest that it integrates multiple signals to coordinate F-actin dynamics with the cellular decision to differentiate or to die. ..
  52. Sheffield M, Loveless T, Hardin J, Pettitt J. C. elegans Enabled exhibits novel interactions with N-WASP, Abl, and cell-cell junctions. Curr Biol. 2007;17:1791-6 pubmed
    ..Instead, our data suggest that Abelson kinase acts in parallel to UNC-34/Ena, antagonizing its function. ..
  53. Sini P, Cannas A, Koleske A, Di Fiore P, Scita G. Abl-dependent tyrosine phosphorylation of Sos-1 mediates growth-factor-induced Rac activation. Nat Cell Biol. 2004;6:268-74 pubmed
    ..Thus, our data identify the molecular connections of a pathway RTKs-Abl-Sos-1-Rac that is involved in signal transduction and actin remodelling. ..
  54. Chodniewicz D, Klemke R. Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffold. Biochim Biophys Acta. 2004;1692:63-76 pubmed
    ..We also highlight the importance of CAS/Crk signaling in the dual regulation of cell migration and survival mechanisms that operate in invasive cells during development and pathological conditions associated with cancer metastasis. ..
  55. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5:172-83 pubmed
    ..What have clinical trials of imatinib and studies using mouse models for BCR-ABL leukaemogenesis taught us about the functions of BCR-ABL beyond its kinase activity, and how these functions contribute to CML pathogenesis? ..
  56. Cowan Jacob S, Fendrich G, Manley P, Jahnke W, Fabbro D, Liebetanz J, et al. The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation. Structure. 2005;13:861-71 pubmed
    ..This structure reveals why the drug shows a low affinity for active kinase conformations, contributing to its excellent kinase selectivity profile. ..
  57. Seeliger M, Young M, Henderson M, Pellicena P, King D, Falick A, et al. High yield bacterial expression of active c-Abl and c-Src tyrosine kinases. Protein Sci. 2005;14:3135-9 pubmed
    ..This method makes practical the use of isotopic labeling of c-Abl and c-Src for NMR studies, and is also applicable for constructs containing the SH2 and SH3 domains of the kinases. ..
  58. Coyne C, Bergelson J. Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell. 2006;124:119-31 pubmed
    ..CVBs thus exploit DAF-mediated signaling pathways to surmount the epithelial barrier. ..
  59. Azam M, Nardi V, Shakespeare W, Metcalf C, Bohacek R, Wang Y, et al. Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance. Proc Natl Acad Sci U S A. 2006;103:9244-9 pubmed
    ..Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IM(R)-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance. ..