Mutant Kinase Reference Guide

Understanding Compound Selectivity in Mutant Kinases

Protein kinases play an integral role as mediators of multiple signal transduction pathways and are responsible for the modulation of essential cellular functions including cell proliferation and differentiation, metabolism and apoptosis. Although many mechanisms have been elucidated by which kinases become uncoupled from normal cellular regulatory processes, mutations have been implicated as causative agents in a diverse range of diseases, including many forms of cancers. These same mechanisms can also confer resistance to therapeutic agents thereby rendering them ineffective and leading to relapse even after initial positive response is observed.

These characteristics can represent hurdles to both the development of efficacious therapies as well as the management of disease progression.  It also suggests a strategy in which compounds, both novel and existing therapeutics, may be comprehensively assessed against disease relevant kinase collections to characterize and understand mechanisms of action and resistance, as well as to identify novel therapeutic opportunities when resistance to first line inhibitors is observed, or as part of a multidrug therapy to eliminate resistance.

Mutant Kinase Disease Association Guide

Mutant Kinase (KGS) Entrez Gene Symbol Kinase Family Significance References
ABL1(E255K) ABL1 TK Mutation confers imatinib-resistance in chronic myeloid leukemia (CML). Lancet. 359, 487-491 (2002).
ABL1(F317I)  ABL1 TK Mutation confers dasatinib-resistance in cell culture. Proc Natl Acad Sci USA. 102, 3395–3400 (2005); Blood. 108, 2332-2338 (2006).
ABL1(F317L) ABL1 TK Mutation confers imatinib- and dasatinib-resistance in chronic myeloid leukemia (CML). Blood. 100, 1014-1018 (2002); J Clin Oncol. 24, e51-52 (2006).
ABL1(H396P) ABL1 TK Mutation confers imatinib- and dasatinib-resistance in chronic myeloid leukemia (CML). Lancet. 359, 487-491 (2002).
ABL1(M351T) ABL1 TK Mutation confers imatinib-resistance in chronic myeloid leukemia (CML). Blood. 100, 1014-1018 (2002).
ABL1(Q252H) ABL1 TK Mutation confers imatinib-resistance in chronic myeloid leukemia (CML). Cancer Cell. 2, 117-125 (2002).
ABL1(T315I) ABL1 TK Mutation confers imatinib-, dasatinib- and nilotinib resistance in chronic myeloid leukemia (CML). Science. 293, 876-880 (2001); Lancet. 359, 487-491 (2002).
ABL1(Y253F) ABL1 TK Mutation confers imatinib-resistance in chronic  myeloid leukemia (CML). Proc Natl Acad Sci USA. 99, 10700-10705 (2002).
BRAF(V600E) BRAF TKL Activating mutation found in malignant melanoma. Nature. 417, 949-954 (2002).
EGFR(E746-A750del) EGFR TK  EGFR inhibitor sensitizing mutation in non-small-cell lung cancer (NSCLC).  N Engl J Med. 350, 2129-2139 (2004); Science. 304, 1497-1500 (2004); Proc Natl Acad Sci USA. 101, 13306-13311 (2004).
EGFR(G719C) EGFR TK EGFR inhibitor sensitizing mutation in non-small-cell lung cancer (NSCLC). N Engl J Med. 350, 2129-2139 (2004).
EGFR(G719S) EGFR  TK  EGFR inhibitor sensitizing mutation in non-small-cell lung cancer (NSCLC). Science. 304, 1497-1500 (2004).
EGFR(L747-E749del, A750P) EGFR TK EGFR inhibitor sensitizing mutation in non-small-cell lung cancer (NSCLC). Science. 304, 1497-1500 (2004).
EGFR(L747-S752del, P753S) EGFR  TK EGFR inhibitor sensitizing mutation in non-small-cell lung cancer (NSCLC).  Science. 304, 1497-1500 (2004).
EGFR(L747-T751del,Sins) EGFR  TK  EGFR inhibitor sensitizing mutation in non-small-cell lung cancer (NSCLC). N Engl J Med. 350, 2129-2139 (2004); Science. 304, 1497-1500 (2004). 
EGFR(L858R) EGFR TK EGFR inhibitor sensitizing mutation in non-small-cell lung cancer (NSCLC). N Engl J Med. 350, 2129-2139 (2004); Science. 304, 1497-1500 (2004); Proc Natl Acad Sci USA. 101, 13306-13311 (2004). 
EGFR(L858R,T790M) EGFR TK  T790M mutation confers ge? tinib- and erlotinib- resistance in non-small-cell lung cancer (NSCLC).  N Engl J Med. 352, 2136 (2005); PLoS Med. 2, e73 (2005). 
EGFR(L861Q) EGFR TK EGFR inhibitor sensitizing mutation in non-small-cell lung cancer (NSCLC). N Engl J Med. 350, 2129-2139 (2004).
EGFR(S752-I759del)  EGFR TK EGFR inhibitor sensitizing mutation in non-small-cell lung cancer (NSCLC). Science. 304, 1497-1500 (2004). 
EGFR(T790M) EGFR TK T790M mutation confers ge? tinib- and erlotinib- resistance in non-small-cell lung cancer (NSCLC). Cancer Res. 66, 7854-7858 (2006). 
FGFR3(G697C) FGFR3 TK Activating mutation found in oral squamous cell carcinoma. Int J Cancer. 117, 166-168 (2005).
FLT3(D835H) FLT3 TK Activating mutation found in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Blood. 97, 2434-2439 (2001); Br J Haematol. 113, 983-988 (2001).  
FLT3(D835Y) FLT3 TK Activating mutation found in acute myeloid leukemia (AML). Blood. 97, 2434-2439 (2001); Br J Haematol. 113, 983-988 (2001).
FLT3(ITD) FLT3 TK Activating mutation found in acute myeloid leukemia (AML). Leukemia. 10, 1911-1918 (1996).
FLT3(K663Q) FLT3 TK Activating mutation found in acute myeloid leukemia (AML). Leukemia. 20, 2008-2014 (2006).
FLT3(N841I) FLT3 TK Activating mutation found in acute myeloid leukemia (AML). Blood. 104, 1855-1858 (2004).
FLT3(R834Q) FLT3 TK Activating mutation found in acute myeloid leukemia (AML). Cancer Cell. 12, 501–513 (2007).
KIT(A829P) KIT TK A829P mutation confers imatinib-resistance in gastrointestinal stromal tumors (GIST). J. Clin. Oncol. 24, 4764-2774 (2006).
KIT(D816H) KIT TK Activating mutation found in systemic mastocytosis, D816H confers imatinib-resistance in gastrointestinal 1542-stromal tumors (GIST). Oncogene. 20, 4528-4536 (2001); Am J Pathol. 163, 305-313 (2004); Proc Natl Acad Sci USA. 106, 1547 (2009).
KIT(D816V) KIT TK Activating mutation found in systemic mastocytosis and acute myeloid leukemia. Nature Gen. 12, 312-314 (1996); Blood 107, 3463-3468 (2006).
KIT(L576P) KIT TK Mutation found in malignant melanoma. Clin Cancer Res. 14 6821-6828 (2008).
KIT(V559D) KIT TK Activating mutation found in gastrointestinal stromal tumors (GIST). Clin. Cancer Res. 11, 3668-3677 (2005).
KIT(V559D,T670I) KIT TK T670I mutation confers imatinib-resistance in gastrointestinal stromal tumors (GIST). Clin. Cancer Res. 11, 4182-4190 (2005).
KIT(V559D,V654A) KIT TK V654A mutation confers imatinib-resistance in gastrointestinal stromal tumors (GIST). Clin. Cancer Res. 11, 4182-4190 (2005).
LRRK2(G2019S) LRRK2 TKL Activating mutation found in Parkinson’s disease. Proc Natl Acad Sci USA. 102, 16842-16847 (2005).
MET(M1250T) MET TK Mutation found drug-resistant papillary renal carcinomas. Proc Natl Acad Sci USA. 95, 14379-14383 (1998); Oncogene. 20, 5493-5502 (2001).
MET(Y1235D) MET TK Activating mutation found in lymph node metastases of head and neck squamous-cell carcinomas. Oncogene. 19, 1547-1555 (2000); Biochemistry. 44, 14110-14119 (2005).
PIK3CA(C420R) PIK3CA LIPID Activating mutation found in diverse cancers. Cancer Res. 65, 4562-4567 (2005); Proc Natl Acad. Sci USA. 104, 5569-5574 (2007).
PIK3CA(E542K) PIK3CA LIPID Activating mutation found in diverse cancers. Proc Natl Acad Sci USA. 103, 1475-1479 (2006); Proc Natl Acad Sci USA. 104, 5569-5574 (2007).
PIK3CA(E545A) PIK3CA LIPID Activating mutation found in diverse cancers. Proc Natl Acad Sci USA. 104, 5569-5574 (2007).
PIK3CA(E545K) PIK3CA LIPID Activating mutation found in diverse cancers. Proc Natl Acad Sci USA. 104, 5569-5574 (2007).
PIK3CA(I800L) PIK3CA LIPID A potential hotspot for resistance mutations. Cancer Cell. 14, 180–192 (2008). Resistant to PI-103 but sensitized to NVP-BEZ-235.
PIK3CA(H1047L) PIK3CA LIPID Activating mutation found in diverse cancers. Proc Natl Acad Sci USA. 104, 5569-5574 (2007).
PIK3CA(H1047Y) PIK3CA LIPID Activating mutation found in diverse cancers. Proc Natl Acad Sci USA. 104, 5569-5574 (2007).
PIK3CA(M1043I) PIK3CA LIPID Activating mutation found in diverse cancers. Cancer Res. 65, 4562-4567 (2005).
PIK3CA(Q546K) PIK3CA LIPID Activating mutation found in diverse cancers. Proc Natl Acad Sci USA. 104, 5569-5574 (2007).
RET(M918T) RET TK Activating mutation found in multiple endocrine neoplasias and familial medullary thyroid carcinomas. Cancer Res. 63, 5559-5563 (2003); Cancer Res. 66, 10741-10749 (2006).
RET(V804L) RET TK Activating mutation found in multiple endocrine neoplasias and familial medullary thyroid carcinomas. Oncogene. 23, 6056-6063 (2004).
RET(V804M) RET TK Activating mutation found in multiple endocrine neoplasias and familial medullary thyroid carcinomas. Oncogene. 23, 6056-6063 (2004).