Future Study of Kinase Inhibitors in Treating Ovarian Cancer

Protein kinases are the largest superfamily of conserved genes in the genome, and many of the family members are implicated in human cancer development. The kinase genes participate in numerous and diverse signaling pathways affecting cellular growth, differentiation, adhesion, motility and survival—all key characteristics of tumorigenesis. Essentially, all structural changes in protein kinases that lead to neoplastic transformation appear to deregulate (constitutively activate) protein kinase activity, providing an attractive target for therapeutic intervention (Table 2-6). For example, therapeutic molecules or proteins have been designed to aim directly

Table 2-6. List of Kinase Genes That Are Promising as Therapeutic Targets for Cancer and Their Small Molecule Inhibitors

No. Official Symbol Gene Name Inhibitor

Table 2-6. List of Kinase Genes That Are Promising as Therapeutic Targets for Cancer and Their Small Molecule Inhibitors

No. Official Symbol Gene Name Inhibitor

1

AKT

v-akt murine thymoma viral oncogene homolog

Naltrindole hydrochloride

2

AURKA

Aurora Kinase A

VX-680

3

AURKB

Aurora Kinase B

VX-680

4

AMPK

AMP-activated protein kinase

Dorsomorphln dlhydrochlorlde

5

CKI

Casein kinase I

D4476

6

CKII

Casein kinase II

DMAT

7

CHK1

Checkpoint kinase I

AZD7762

8

CHK2

Checkpoint kinase II

AZD7762

9

CDK2

Cyclin-dependent kinase 2

Sellclcllb (CYC202, R-roscovltlne)

10

CDK7

Cyclin-dependent kinase 7

Sellclcllb (CYC202, R-roscovltlne)

11

CDK9

Cyclin-dependent kinase 9

Sellclcllb (CYC202, R-roscovltlne)

12

DNAPK

DNA-dependent protein kinase

NU7441

13

GSK3A

Glycogen synthase kinase 3 alpha

BIO (2'Z,3'E)-6-Bromolndlrubln-3'-oxlme

14

GSK3B

Glycogen synthase kinase 3 beta

BIO (2'Z,3'£)-6-Bromolndlrubln-3'-oxlme

15 JNK1

16 JNK2

17 JNK3

18 ERK1

19 ERK2

20 p38 MAPK

21 MEK1

22 MEK2

23 PI3K

24 PKA

25 PKCa

28 PKCS

c-Jun N-terminal kinase 1

c-Jun N-terminal kinase 2

c-Jun N-terminal kinase 3

Extracellular signal-regulated kinase 1

Extracellular signal-regulated kinase 2

p38 Mitogen-activated protein kinase

Mitogen-activated protein kinase kinase 1

Mitogen-activated protein kinase kinase 2

Phosphatidylinositol 3-kinase

Protein kinase A, cAMP-dependent protein kinase

Protein kinase C alpha-isozyme

Protein kinase C beta 1-isozyme

Protein kinase C beta 2-isozyme

Protein kinase C delta-isozyme

SP600125 SP600125 SP600125 PD98059

PD98059

SB203580

U0126

U0126

LY294002

H89 dlhydrochlorlde

Go6976

LY379196

LY379196

Rottlerin

Table 2-6. List of Kinase Genes That Are Promising as Therapeutic Targets for Cancer and Their Small Molecule Inhibitors—cont'd

No.

Official Symbol

Gene Name

Inhibitor

29

PKCe

Protein kinase C epsilon-isozyme

GF 109203X (Bisindolylmaleimide I)

30

PKGIa

cGMP-dependent protein kinase type I alpha

Rp-8-pCPT-cGMPS, TEA

31

PKGIp

cGMP-dependent protein kinase type I beta

Rp-8-pCPT-cGMPS, TEA

32

PKGII

cGMP-dependent protein kinase type II

Rp-8-pCPT-cGMPS, TEA

33

Plk1

Polo-like kinase 1

BI 2536

34

PDGFRa

Platelet-derived growth factor receptor alpha

Gleevec (imatinib)*

35

BCR-ABL

BCR-ABL kinase

Gleevec (imatinib)*

36

c-Kit

v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog

Sutent (sunitinib)*

37

SRC

v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)

Sprycel (dasatinib)*

38

EPHA2

Ephrin receptor A2

Sprycel (dasatinib)*

39

EGFR

Epidermal growth factor receptor

Iressa (gefitinib)*

40

ERBB2

v-erb-b2 erythroblastic leukemia viral oncogene homolog 2

Tykerb (lapatinib)*

41

VEGFR1

Vascular endothelial growth factor receptor 1

Recentin (Cediranib)

42

VEGFR2

Vascular endothelial growth factor receptor 2

Recentin (Cediranib)

43

VEGFR3

Vascular endothelial growth factor receptor 3

Recentin (Cediranib)

44

RET

ret proto-oncogene

Zactima (vandetanib)+

45

IGF1R

Insulin-like growth factor 1 receptor

OSI-906

46

JAK2

Janus-activated kinase 2

Lestaurtinib (CEP-701)

47

JAK3

Janus-activated kinase 3

CP-690550

48

STAT3

Signal transducers and activators of transcription 3

Cucurbitacin I (JSI-124)

49

STAT5

Signal transducers and activators of transcription 5

Lestaurtinib (CEP-701)

50

FGFR1

Fibroblast growth factor receptor 1

SU5402

51

FGFR2

Fibroblast growth factor receptor 2

PD173074

52

Lck

Lymphocyte-specific protein tyrosine kinase, p56

Emodin

Table continued

Table 2-6. List of Kinase Genes That Are Promising as Therapeutic Targets for Cancer and Their Small Molecule Inhibitors—cont'd

No.

Official Symbol

Gene Name

Inhibitor

53

c-Met

Met proto-oncogene (hepatocyte growth factor receptor)

ARQ 197

54

SYK

Spleen tyrosine kinase

R406

55

TGFßRI

Transforming growth factor ß type I receptor

SM16

56

TrkA

Neurotrophic tyrosine kinase, receptor, type 1

GW 441756

57

c-Raf

v-raf-1 murine leukemia viral oncogene homolog 1

Sorafenib (BAY43-9006)*

58

B-Raf

v-raf murine sarcoma viral oncogene homolog B1

Sorafenib (BAY43-9006)*

59

ROCK1

Rho-associated, coiled-coil containing protein kinase 1

Fasudil

60

ROCK2

Rho-associated, coiled-coil containing protein kinase 2

Fasudil

61

SK

Sphingosine kinase

Dimethylsphingosine (DMS)

* FDA-approved anti-cancer drugs. f FDA fast track designation received.

* FDA-approved anti-cancer drugs. f FDA fast track designation received.

at inhibiting protein kinase activity such as STI571 (Gleevec), an ATP-binding competitive inhibitor that is a potent inhibitor of the BCR-Abl and c-KIT tyrosine kinases. Gleevec is now used to treat chronic myelogenous leukemia and gastrointestinal stromal tumors with promising antitumor effect.60 A number of other protein kinase inhibitors are in clinical trials for a variety of malignancies and other diseases (see Table 2-6). In most serous borderline tumors and low-grade serous carcinomas of the ovary, there is constitutive activation of the MAPK signaling pathway owing to frequent mutations in the KRAS and BRAF genes, the upstream regulators of MAPK. Accordingly, it is interesting to test whether BRAF inhibitors and other MEK inhibitors can prolong disease-free interval and overall survival in patients with advanced-stage serous borderline tumors. Further identification and characterization of the panoply of molecular changes associated with ovarian carcinogenesis will facilitate development of diagnostic tests for early detection of ovarian cancer and for the development of novel therapies aimed at blocking key growth-signaling pathways.

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