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DRUG RECORD

 

KINASE INHIBITORS

OVERVIEW
Protein Kinase Inhibitors

 

The kinase inhibitors are a large group of unique and potent antineoplastic agents which specifically target protein kinases that are altered in cancer cells and that account for some of their abnormal growth.  Protein kinases are ubiquitous intracellular and cell surface proteins that play critical roles in cell signaling pathways involved in metabolism, injury responses, adaption, growth and differentiation.  They act by adding a phosphate group to a protein (phosphorylation), usually on a specific amino acid which often makes the protein or enzyme "active".  The human genome has more than 500 protein kinases and they can be classified as (1) tyrosine, (2) serine-theonine or (3) nonspecific (both), based upon their amino acid specificity.  Many protein kinases are cell surface receptors and act to initiate an intracellular pathway of activation, after the receptor is engaged by its ligand, typically a cytokine or growth factor.  Inhibitors of these kinases are called protein kinase receptor inhibitors.  Other kinases are intracellular and take part in cell signaling.  These kinases can be targeted by "non-receptor" protein kinases.  Finally, some kinase inhibitors have specificity for multiple kinases and are called "multi-kinase inhibitors."

 

Protein kinases can be specifically involved in cell growth, proliferation and differentiation and mutations may lead to unregulated growth and proliferation that is typical of cancerous cells. These mutated protein kinases represent an attractive target for anticancer agents.  The potent activity and lack of generalized toxicity of the kinase inhibitors relate to the specificity of antagonist for the mutated protein.  In like manner, their toxicity often relates to off-target activity, either to the unmutated kinase or to closely related, normal kinases.

 

The protein kinases can be categorized based upon the amino acid that they phosphorylate:  either serine, threonine or tyrosine.  The tyrosine kinase receptor inhibitors were the initial and are perhaps the best characterized kinase inhibitors.  The protein kinase inhibitors are relatively recently developed agents, all having been introduced since 2001.  They are unique and represent a major advance in cancer chemotherapy, away from broadly cytotoxic agents and towards drugs that specifically target the molecular abnormalities of cancer cells.  The initial tyrosine kinase inhibitor approved for use in the United States was imatinib (Gleevec: 2001) which is used to treat Philadelphia chromosome positive chronic lymphocytic leukemia, which has a mutated kinase receptor (BCR-ABL) that is created by the specific translocation that creates the Philadelphia chromosome.  Imatinib is a specific inhibitor of the BCR-ABL kinase.  The introduction of this first protein kinase inhibitor was followed by more than a dozen others within the next 10 years.

 

While most kinase inhibitors are antineoplastic agents, a few are also used for benign conditions including macular degeneration (pegaptanib), rheumatoid arthritis (tofacitinib) and idiopathic pulmonary fibrosis (nintedanib).  Generally, however, the side effect profile of kinase inhibitors are such that they are reserved for severe, progressive, debilitating or potentially fatal conditions.

 

The protein kinase inhibitors all have some degree of hepatotoxicity and many have been linked to cases of clinically apparent liver injury which can be severe and even fatal (Table).  Interestingly, some of the cases of liver injury attributed to the protein kinase antagonists had features of autoimmunity, so that the liver injury may be caused by an immunologic reaction to metabolic products of the agent itself, rather than off-target activity of the inhibitor.  In addition, at least two protein kinase inhibitors (imatinib and nilotinib) have been linked to instances of reactivation of hepatitis B.  It is not clear whether this relates to a specific activity of the kinase inhibitor on hepatitis B virus replication or whether it is due to immunosuppression.  Other kinase inhibitors have been linked to cases of rare and idiosyncratic liver injury, which can be hepatocellular or cholestatic and is typically self-limited but may be fatal.

 

The Table below lists the protein kinase inhibitors discussed in LiverTox, their brand name, predominant protein kinase (PK) specificity, major clinical uses, year of approval in the United States, likelihood score and whether they have been implicated in cases of fatal acute liver injury.  Following the Table are the specific agents that are discussed individually, each with relevant references to their safety and hepatotoxicity.

PROTEIN KINASE INHIBITORS*

Generic Name

Brand Name

Kinase Major Uses Approval

Likelihood

Score

Fatalities

Afatinib

Gilotrif

EGFR, HER2

NSCLC

2013 D No

Alectinib

Alecensa

ALK

NSCLC

2015 D No

Axitinib

Inlyta

VEGFR 1-3

Renal cell cancer

2012

E

No

Bortezomib

Velcade

Proteasome

Multiple myeloma, Mantle cell lymphoma

2003

C

Yes

Bosutinib

Bosulif

BCR-ABL, scr

CML, resistant

2012

E*

No

Cabozantinib

Cometriq, Cabometyx

MET, VEGFR-2

Medullary thyroid cancer, Renal cell cancer

2012 E* No

Carfilzomib

Kyprolis

Proteasome

Multiple myeloma, resistant

2012

E*

Yes

Ceritinib

Zykadia

ALK

NSCLC

2014 D No

Cobimetinib

Cotellic

MEK

Malignant melanoma

2015 D No

Crizotinib

Xalkori

ALK

NSCLC

2011

D

Yes

Dabrafenib

Tafinlar

BRAF

Melanoma

2013

E*

No

Dasatinib

Sprycel

BCR-ABL, src

CML, resistant

2006

D

No

Erlotinib

Tarceva

EGFR, HER1

NSCLC, Pancreatic cancer

2004

C

No

Gefitinib

Iressa

EGFR

NSCLC

2009

C

No

Ibrutinib

Imbruvica

Bruton kinase

Mantle cell lymphoma, CLL

2013

D

No

Idelalisib

Zydelig

PI3Kδ

CLL, Non-Hodgkin lymphoma

2014 D No

Imatinib

Gleevec

BCR-ABL, c-Kit

CML, GIST

2001

B

Yes

Ixazomib

Ninlaro

26S Proteasome

Multiple myeloma

2015 E* Yes

Lapatinib

Tykerb

EGFR, HER2

Breast cancer, HER2 positive

2007

D

Yes

Lenvatinib

Lenvima

VEGFR 1-3, FGF 1-4, PDGF, c-Kit, RET

Thyroid cancer, Renal cell cancer

2015/16 D Yes

Nilotinib

Tasigna

BCR-ABL

CML, resistant

2007

E*

No

Nintedanib

Ofev

VEGFR, FGFR, PDGF

Pulmonary fibrosis

2014 E* No

Niraparib

Zejula

PARP

Ovarian cancer

2017 E* No

Olaparib

Lynparza

PARP

Ovarian cancer, advanced, refractory, Breast cancer

2014 2018 E No

Osimertinib

Tagrisso

EGFR

NSCLC, refractory

2015 E* No

Palbociclib

Ibrance

ER+, HER2

Breast cancer, HER2 negative

2015 E* No

Pazopanib

Votrient

VEGFR 1-3

Renal cell cancer

2009

C

Yes

Pegaptanib

Macugen

VEGFR 1-3

Macular degeneration

2004

E

No

Ponatinib

Iclusig

BCR-ABL

CML, ALL

2013

E*

Yes

Regorafenib

Stivarga

VEGFR 1-3, PDGF

Colorectal cancer, GIST

2012

D

Yes

Ribociclib

Kisqali

Cyclin dependent kinase 4/6

Breast cancer

2017 C No

Rucaparib

Rubraca

PARP

Ovarian cancer, advanced

2016 D* No

Ruxolitinib

Jakafi

Janus kinase

Myelofibrosis

2011

E*

No

Sonidegib

Odomzo

Hedgehog

Basal cell skin cancer

2015 E* No

Sorafenib

Nexavar

VEGFR 1-3

Renal cell and hepatocellular cancer

2005

C

No

Sunitinib

Sutent

PDGF, c-Kit

CML, resistant; GIST, renal cell cancer

2006

D

Yes

Tofacitinib

Xeljanz

Janus kinase

Rheumatoid arthritis

2012 E* No

Trametinib

Mekinist

MEK 1-2

Malignant melanoma

2013

E*

No

Vandetanib

Caprelsa

VEGFR 2

Medullary thyroid cancer

2011

E*

No

Vemurafenib

Zelboraf

BRAF

Malignant melanoma

2011

E*

No

Vismodegib

Erivedge

Hedgehog

Basal cell skin cancer

2012

D

No

* Abbreviations:  ALL, acute lymphocytic leukemia; CLL, Chronic lymphocytic

   leukemia; CML, chronic myelogenous leukemia; GIST, gastrointestinal

   stromal tumor; NSCLC, non-small cell lung cancer.

Likelihood Score indicates the likelihood of association with drug induced

   liver injury, based upon the known potential of the drug to cause such injury.

 

Protein Kinase Inhibitors:  Afatinib, Alectinib, Axitinib, Bortezomib, Bosutinib, Cabozantinib, Carfilzomib, Ceritinib, Cobimetinib, Crizotinib, Dabrafenib, Dasatinib, Erlotinib, Gefitinib, Ibrutinib, Idelalisib, Imatinib, Ixazomib, Lapatinib, Lenvatinib, Nilotinib, Nintedanib, Niraparib, Olaparib, Osimertinib, Palbociclib, Pazopanib, Ponatinib, Regorafenib, Ribociclib, Rucaparib, Ruxolitinib, Sonidegib, Sorafenib, Sunitinib, Tofacitinib, Trametinib, Vandetanib, Vemurafenib, Vismodegib

 

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