Developments in anaplastic large-cell lymphoma: targeting the anaplastic lymphoma kinase

Figures & data

Table 1 Chromosomal rearrangements involving the ALK gene and producing oncogenic fusion proteins in anaplastic large-cell lymphomas and other cancers

Gene	Translocation	Frequency in ALK+ anaplastic large-cell lymphomas	Localization	Reference
NPM	t(2;5)(p23,q35)	78%	Nuclear/cytoplasmic	112–114
ATIC	Inv(2)(p23,q35)	2%	Cytoplasmic	115,116
ALOI7	t(2;17)(p23;q25)	1%	Cytoplasmic	117,118
CARS	t(2;11)(p23;p15)	Unknown	Unknown	117,119
CTLC	t(2;17)(p23;q23)	2%	Cytoplasmic	120,121
MYH-9	t(2;22)(p23;q11.2)	1%	Cytoplasmic	118,121
MSN	t(2,X)(p23,q1)	1%	Membrane of the cell	122,123
TFG	t(2,3)(p23,q21)	1%	Cytoplasmic	124,125
TPM3	t(1,2)(q25,p23)	18%	Cytoplasmic	126
TPM4	t(2,19)(p23,p13)	1%	Cytoplasmic	127
RANBP2	t(2,2)(p23,q11)	Unknown	Nuclear membrane	128
SEC3ILI	t(2;4)(p23;q21)	Unknown	Cytoplasmic	129
EML4	Inv(2)(p21,p23)	Unknown	Cytoplasmic	130,131
KIF5B	t(2;10)(p23;p11)	Unknown	Cytoplasmic	132
SQSTMI	t(2;5)(p23.1;q35.3)	Unknown	Granules cytoplasmic	133

Abbreviation: ALK, anaplastic lymphoma kinase.

Table 2 Inhibitors of anaplastic lymphoma kinase in development^{26,139,147–149}

Name	Therapeutics	Responses	Trials in NHLs	Clinical trials ongoing, references and notes
PF-02341066 (crizotinib;	Selective ATP competitive oral	Overall response rate 91%	Yes	Phase I-II done;^Citation90
Pfizer, Inc., New York, NY, USA)	inhibitor of ALK and c-MET tyrosine kinases and their variants	with 9/11 complete response^Citation25		ongoing phase III; studies with crizotinib as single agent or in combination
AP-26113 (Ariad, Cambridge, MA, USA)	Dual ALK/epidermal growth factor receptor inhibitor AP- 26113 is 10-fold more potent compared with PF-02341066	67% overall response rate with 2/15 complete response in non-small-cell lung cancer^Citation134	Yes	Well-tolerated; phase I/II^Citation134
ASP 3026 (Astellas Pharma, Northbrook, iL, USA)	Dual ALK/epidermal growth factor receptor inhibitor		Yes	Phase I: promising safety and tolerability^Citation135
LDK 378 (Novartis, Basel, Switzerland)	Selective ALK inhibitor	Durable responses in the majority of patients with advanced, ALK+ non-small-cell lung cancer, including crizotinib-resistant patients with and without crizotinib resistance mutations;^Citation107 overall response rate, 70%^Citation136	Yes	Phase I: safety in ALK positive/genetically abnormal tumors; preliminary results^Citation136,Citation137
NPv-TAE684 (TAE-684) (Novartis, genomics institut of the Novartis research foundation) CEP-28122 (Cephalon, Frazer, PA, USA) F91873 and F91874 (istitut de rechercher Pierre Fabre) PHA-E429 (Nerviano Medical Science)	Selective ALK inhibitor; good oral bioavailability in vivo (60%-70%) Selective ALK inhibitor ATP noncompetitive inhibitors, pyridoisoquinoline derivatives ATP competitive, crystal structure of the ALK kinase domain in a complex with PHA-E429		No	Phase I discontinued^Citation137 Preclinical^Citation138 Preclinical Preclinical/phase I^Citation139
CEP-14083 and Cep-14513 (Cephalon)	Selective ALK inhibitor		No	Phase I
NMS-E628 (Ariad)	ALK inhibitor		No	Phase I^Citation140
wZ-5-12 (Ambit Biosciences)	ALK small molecules inhibitor			Preclinical^Citation141
CRL151104	ATP competitor			Preclinical^Citation41
(Chebridge St. Jude)
CH5424802 (Chugai Pharmaceutical, Tokyo, Japan; Roche, Basel, Switzerland)	Potent and selective orally available ALK inhibitor^Citation142^–^Citation143	Overall response rate 93% with 2/46 complete response and durable treatment^Citation144	No	Mild toxicity; phase I/II trial in non-small-cell lung cancer patients in Japan^Citation144
X396 (XCovery, west Palm Beach, FL, USA)		Pharmacokinetic properties and toxicity profiles are favorable		Phase I^Citation145
GSK1838705A (GlaxoSmithKline, Brentford, United Kingdom)	Small-molecule kinase inhibitor of insulin-like growth factor; receptor. Abrogates ALK, and growth of anaplastic large cell lymphoma			Preclinical^Citation146

Abbreviations: ATP, adenosine triphosphate; ALK, anaplastic lymphoma kinase; NHLs, non Hodgkin lymphomas.

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