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Ref Type | Journal Article | ||||||||||||
PMID | (28077790) | ||||||||||||
Authors | Nguyen B, Williams AB, Young DJ, Ma H, Li L, Levis M, Brown P, Small D | ||||||||||||
Title | FLT3 activating mutations display differential sensitivity to multiple tyrosine kinase inhibitors. | ||||||||||||
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URL | |||||||||||||
Abstract Text | Fms-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that normally functions in hematopoietic cell survival, proliferation and differentiation. Constitutively activating mutations of FLT3 map predominately to the juxtamembrane domain (internal tandem duplications; ITD) or the activation loop (AL) of the kinase domain and are detected in about 1/3 of de novo acute myeloid leukemia (AML) patients. Small molecule tyrosine kinase inhibitors (TKI) effectively target FLT3/ITD mutations, but some activating mutations, particularly those on the AL, are relatively resistant to many FLT3 TKI. We reproduced many of the AL or other non-ITD activating mutations and tested 13 FLT3 TKI for their activity against these and wild-type FLT3. All 13 TKI tested inhibited BaF3/ITD cell proliferation in a concentration-dependent manner as reported, but most TKI exhibited a wide range of differential activity against AL and other point mutants. Western blotting results examining inhibition of FLT3 autophosphorylation and signaling pathways indicate that many AL mutations reduce TKI binding. Most FLT3 TKI effectively target wild-type FLT3 signaling. As a demonstration of this differential activity, treatment of BaF3 D835Y cells transplanted in BALB/c mice with sorafenib showed no effect in vivo against this mutant whereas lestaurtinib proved effective at reducing disease burden. Thus, while FLT3 TKI have been selected based on their ability to inhibit FLT3/ITD, the selection of appropriate TKI for AML patients with FLT3 AL and other activating point mutations requires personalized consideration. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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No data available in table |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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FLT3 | D835G | missense | gain of function - predicted | FLT3 D835G lies within the activation loop in the protein kinase domain of the Flt3 protein (PMID: 25837374). D835G results in autophosphorylation of Flt3 in cultured cells (PMID: 28077790), and therefore, is predicted to lead to a gain of Flt3 protein function. | |
FLT3 | D835K | missense | gain of function - predicted | FLT3 D835K lies within the activation loop in the protein kinase domain of the Flt3 protein (PMID: 25837374). D835K results in IL3-independent growth in culture (PMID: 28077790), and therefore, is predicted to lead to a gain of Flt3 protein function. | |
FLT3 | D835L | missense | gain of function - predicted | FLT3 D835L lies within the activation loop in the protein kinase domain of the Flt3 protein (PMID: 25837374). D835L results in IL3-independent growth in culture (PMID: 28077790), and therefore, is predicted to lead to a gain of Flt3 protein function. | |
FLT3 | I836D | missense | gain of function | FLT3 I836D lies within the protein kinase domain of the Flt3 protein (UniProt.org). I836D results in IL3-independent growth in culture (PMID: 28077790), and therefore, is predicted to lead to a gain of Flt3 protein function. | |
FLT3 | I836L | missense | gain of function - predicted | FLT3 I836L lies within the protein kinase domain of the Flt3 protein (UniProt.org). I836L results in IL3-independent growth in culture (PMID: 28077790), and therefore, is predicted to lead to a gain of Flt3 protein function. | |
FLT3 | I836S | missense | gain of function - predicted | FLT3 I836S lies within the protein kinase domain of the Flt3 protein (UniProt.org). I836S results in IL3-independent growth in culture (PMID: 28077790), and therefore, is predicted to lead to a gain of Flt3 protein function. | |
FLT3 | I836T | missense | gain of function - predicted | FLT3 I836T lies within the protein kinase domain of the Flt3 protein (UniProt.org). I836T results in IL3-independent growth in culture (PMID: 28077790), and therefore, is predicted to lead to a gain of Flt3 protein function. |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
FLT3 D835A | hematologic cancer | no benefit | Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Nexavar (sorafenib) did not inhibit viability in transformed cells expressing FLT3 D835A in culture (PMID: 28077790). | 28077790 |
FLT3 D835A | hematologic cancer | no benefit | Tamatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Tamatinib (R406) did not inhibit viability of transformed cells expressing FLT3 D835A in culture (PMID: 28077790). | 28077790 |
FLT3 D835A | hematologic cancer | no benefit | AG1295 | Preclinical - Cell culture | Actionable | In a preclinical study, AG1295 did not inhibit viability of transformed cells expressing FLT3 D835A in culture (PMID: 28077790). | 28077790 |
FLT3 D835A | hematologic cancer | no benefit | Quizartinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vanflyta (quizartinib) did not inhibit viability of transformed cells expressing FLT3 D835A in culture (PMID: 28077790). | 28077790 |
FLT3 D835A | hematologic cancer | no benefit | Linifanib | Preclinical - Cell culture | Actionable | In a preclinical study, Linifanib (ABT-869) did not inhibit viability of transformed cells expressing FLT3 D835A in culture (PMID: 28077790). | 28077790 |
FLT3 D835A | hematologic cancer | sensitive | Lestaurtinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lestaurtinib (CEP-701) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835A in culture (PMID: 28077790). | 28077790 |
FLT3 D835A | hematologic cancer | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835A in culture (PMID: 28077790). | 28077790 |
FLT3 D835A | hematologic cancer | no benefit | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) did not inhibit viability of transformed cells expressing FLT3 D835A in culture (PMID: 28077790). | 28077790 |
FLT3 D835A | hematologic cancer | sensitive | KW-2449 | Preclinical - Cell culture | Actionable | In a preclinical study, KW-2449 inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835A in culture (PMID: 28077790). | 28077790 |
FLT3 D835G | hematologic cancer | sensitive | Linifanib | Preclinical - Cell culture | Actionable | In a preclinical study, Linifanib (ABT-869) inhibited viability in transformed cells expressing FLT3 D835G in culture (PMID: 28077790). | 28077790 |
FLT3 D835G | hematologic cancer | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) inhibited viability in transformed cells expressing FLT3 D835G in culture (PMID: 28077790). | 28077790 |
FLT3 D835G | hematologic cancer | sensitive | Ponatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835G in culture (PMID: 28077790). | 28077790 |
FLT3 D835G | hematologic cancer | sensitive | Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Nexavar (sorafenib) inhibited viability in transformed cells expressing FLT3 D835G in culture (PMID: 28077790). | 28077790 |
FLT3 D835G | hematologic cancer | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835G in culture (PMID: 28077790). | 28077790 |
FLT3 D835G | hematologic cancer | sensitive | Lestaurtinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lestaurtinib (CEP-701) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835G in culture (PMID: 28077790). | 28077790 |
FLT3 D835G | hematologic cancer | sensitive | KW-2449 | Preclinical - Cell culture | Actionable | In a preclinical study, KW-2449 inhibited viability in transformed cells expressing FLT3 D835G in culture (PMID: 28077790). | 28077790 |
FLT3 D835G | hematologic cancer | sensitive | Quizartinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vanflyta (quizartinib) inhibited viability in transformed cells expressing FLT3 D835G in culture (PMID: 28077790). | 28077790 |
FLT3 D835G | hematologic cancer | sensitive | Crenolanib | Preclinical - Cell culture | Actionable | In a preclinical study, Crenolanib (CP-868596) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835G in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | no benefit | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) did not inhibit viability of transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | no benefit | KW-2449 | Preclinical - Cell culture | Actionable | In a preclinical study, KW-2449 did not inhibit viability of transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | no benefit | Linifanib | Preclinical - Cell culture | Actionable | In a preclinical study, Linifanib (ABT-869) did not inhibit viability of transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | no benefit | Crenolanib | Preclinical - Cell culture | Actionable | In a preclinical study, Crenolanib (CP-868596) did not inhibit viability of transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | sensitive | Lestaurtinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lestaurtinib (CEP-701) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | no benefit | Quizartinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vanflyta (quizartinib) did not inhibit viability of transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | no benefit | Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Nexavar (sorafenib) did not inhibit viability of transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | no benefit | Ponatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Iclusig (ponatinib) did not inhibit viability of transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | no benefit | Tamatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Tamatinib (R406) did not inhibit viability of transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835K FLT3 D835L | hematologic cancer | no benefit | AG1295 | Preclinical - Cell culture | Actionable | In a preclinical study, AG1295 did not inhibit viability of transformed cells expressing FLT3 D835L and D835K in culture (PMID: 28077790). | 28077790 |
FLT3 D835N | hematologic cancer | sensitive | Crenolanib | Preclinical - Cell culture | Actionable | In a preclinical study, Crenolanib (CP-868596) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835N in culture (PMID: 28077790). | 28077790 |
FLT3 D835N | hematologic cancer | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835N in culture (PMID: 28077790). | 28077790 |
FLT3 D835N | hematologic cancer | sensitive | Linifanib | Preclinical - Cell culture | Actionable | In a preclinical study, Linifanib (ABT-869) inhibited viability in transformed cells expressing FLT3 D835N in culture (PMID: 28077790). | 28077790 |
FLT3 D835N | hematologic cancer | sensitive | Lestaurtinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lestaurtinib (CEP-701) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835N in culture (PMID: 28077790). | 28077790 |
FLT3 D835N | hematologic cancer | sensitive | Ponatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 D835N in culture (PMID: 28077790). | 28077790 |
FLT3 D835N | hematologic cancer | sensitive | Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Nexavar (sorafenib) inhibited viability in transformed cells expressing FLT3 D835N in culture (PMID: 28077790). | 28077790 |
FLT3 D835N | hematologic cancer | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) inhibited viability in transformed cells expressing FLT3 D835N in culture (PMID: 28077790). | 28077790 |
FLT3 D835N | hematologic cancer | sensitive | Quizartinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vanflyta (quizartinib) inhibited viability in transformed cells expressing FLT3 D835N in culture (PMID: 28077790). | 28077790 |
FLT3 D835N | hematologic cancer | sensitive | KW-2449 | Preclinical - Cell culture | Actionable | In a preclinical study, KW-2449 inhibited viability in transformed cells expressing FLT3 D835N in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | no benefit | Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Nexavar (sorafenib) did not inhibit viability of transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | sensitive | Crenolanib | Preclinical - Cell culture | Actionable | In a preclinical study, Crenolanib (CP-868596) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | no benefit | Tamatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Tamatinib (R406) did not inhibit viability of transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | no benefit | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) did not inhibit viability of transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | sensitive | Ponatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Iclusig (ponatinib) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | no benefit | Quizartinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vanflyta (quizartinib) did not inhibit viability of transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | sensitive | Lestaurtinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lestaurtinib (CEP-701) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | no benefit | Linifanib | Preclinical - Cell culture | Actionable | In a preclinical study, Linifanib (ABT-869) did not inhibit viability of transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | no benefit | KW-2449 | Preclinical - Cell culture | Actionable | In a preclinical study, KW-2449 did not inhibit viability of transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836D FLT3 I836L | hematologic cancer | no benefit | AG1295 | Preclinical - Cell culture | Actionable | In a preclinical study, AG1295 did not inhibit viability of transformed cells expressing FLT3 I836D and I836L in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | no benefit | Quizartinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vanflyta (quizartinib) did not inhibit viability of transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | no benefit | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) did not inhibit viability of transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | no benefit | Tamatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Tamatinib (R406) did not inhibit viability of transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | no benefit | Linifanib | Preclinical - Cell culture | Actionable | In a preclinical study, Linifanib (ABT-869) did not inhibit viability of transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | no benefit | AG1295 | Preclinical - Cell culture | Actionable | In a preclinical study, AG1295 did not inhibit viability of transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | no benefit | Crenolanib | Preclinical - Cell culture | Actionable | In a preclinical study, Crenolanib (CP-868596) did not inhibit viability of transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | no benefit | KW-2449 | Preclinical - Cell culture | Actionable | In a preclinical study, KW-2449 did not inhibit viability of transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | sensitive | Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Nexavar (sorafenib) inhibited viability in transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836S | hematologic cancer | sensitive | Lestaurtinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lestaurtinib (CEP-701) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 I836S in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | sensitive | Quizartinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vanflyta (quizartinib) inhibited viability in transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | sensitive | Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Nexavar (sorafenib) inhibited viability in transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | sensitive | Lestaurtinib | Preclinical - Cell culture | Actionable | In a preclinical study, Lestaurtinib (CEP-701) inhibited Flt3 autophosphorylation and viability in transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | no benefit | Ponatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Iclusig (ponatinib) did not inhibit viability of transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | no benefit | Crenolanib | Preclinical - Cell culture | Actionable | In a preclinical study, Crenolanib (CP-868596) did not inhibit viability of transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | sensitive | Linifanib | Preclinical - Cell culture | Actionable | In a preclinical study, Linifanib (ABT-869) inhibited viability in transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | no benefit | AG1295 | Preclinical - Cell culture | Actionable | In a preclinical study, AG1295 did not inhibit viability of transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | sensitive | KW-2449 | Preclinical - Cell culture | Actionable | In a preclinical study, KW-2449 inhibited viability in transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
FLT3 I836T | hematologic cancer | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) inhibited viability in transformed cells expressing FLT3 I836T in culture (PMID: 28077790). | 28077790 |
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