New developments in management of gastrointestinal stromal tumors: regorafenib, the new player in the team

Figures & data

Table 1 Comparison of the kinase inhibitory profiles of imatinib, sunitinib, sorafenib, and regorafenib

Imatinib	Sunitinib	Sorafenib	Regorafenib
KIT	KIT	KIT	KIT
PDGFRA	PDGFRA	PDGFRB	PDGFRB
PDGFRB	PDGFRB	VEGFR-2	VEGFR-1
ABL (BCR-ABL)	VEGFR-1	VEGFR-3	VEGFR-2
	VEGFR-2	RAF-1	VEGFR-3
	VEGFR-3	BRAF	RAF-1
	RET	FGFR-1	BRAF
	FGFR-1	FLT-3	FGFR-1
	CSF-1R		TIE-2 RET p38 MAPK

Abbreviations: BCR-ABL, break point cluster region-Abelson; BRAF, v-RAF murine sarcoma viral oncogene homolog B1; CSF-1R, colony stimulating factor 1 receptor; FGFR-1, fibroblast growth factor receptor-1; FLT-3, FMS-related tyrosine kinase 3; KIT, kitten; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; RAF-1, v-RAF-1 murine leukemia viral oncogene homolog; RET, rearranged during transfection; TIE, tyrosine kinase with immunoglobulin and EGF factor homology domains; VEGFR, vascular endothelial growth factor receptor.

Table 2 Emerging therapies for GIST

Target pathway	Target molecule(s)	Compound	Trade name	Company
KIT/PDGFR	KIT, PDGFRB, BCR-ABL, LCK, EPHA3/8, DDR1/2, MAPK11, ZAK	Nilotinib (AMNI07)^a	Tasigna®	Novartis
	KIT, PDGFRB, VEGFR2/3, RAF-1, BRAF, FGFR1, FLT3, RET	Sorafenib tosylate (BAY 43-9006)	Nexavar®	Bayer
	KIT, PDGFRA/B, BCR-ABL, SRC	Dasatinib (BMS-354825)^d	Sprycel®	Bristol-Myers Squibb
	KIT, PDGFRA/B, VEGFR1/2/3	Pazopanib	Votrient®	GlaxoSmithKline
	KIT, PDGFRA/B, LYN, FGFR3	Masitinib (AB1010)	Kinavet®	AB Science
	KIT, PDGFRA, VEGFR2, FGFR1, BCR-ABL, FLT3, RET, EPH, TIE2	Ponatinib	Iclusig®	Ariad Pharmaceuticals
	KIT, PDGFRB, VEGFR1/2/3	Vatalanib (PTK787/ZK222584)	–	Bayer
	KIT, PDGFRA/B, VEGFR1/2/3	Motesanib (AMG 706)	–	Amgen
	KIT, PDGFRB, VEGFR2	XL820	–	Exelixis
	KIT, PDGFRB, VEGFR1/2/3	OSI-930	–	Astellas Pharma/OSI Pharmaceuticals
	KIT, VEGFR1/2/3, FLT3, FGFR1/2/3	Dovitinib (TKI258)	–	Novartis
PDGFRA D842V	PDGFRA D842V (PDGFRA/B, FLT3)	Crenolanib besylate (CP-868,596)^g	–	Arog Pharmaceuticals
	PDGFRA	Olaratumab (IMC-3G3)^f	–	ImClone
VEGFR	VEGF-A	Bevacizumab^b,^f	Avastin®	Genetech/Roche
IGFR	IGF-IR, IR	Linsitinib (OSI-906)	–	Astellas Pharma/OSI Pharmaceuticals
EGFR	EGFR	Erlotinib (CP-358,774, OSI-774)^b	Tarceva®	Genentech/Roche
	EGFR	Cetuximab^e^f	Erbitux®	Bristol-Myers Squibb
P13K	P13K	BYL719^b	–	Novartis
	P13K	BKM120^b	–	Novartis
	PI3K, AKT	Perifosine^b	–	Aeterna Zentaris
mTOR	mTOR	Everolimus (RAD001)^a	Afinitor®	Novartis
	mTOR	Temsirolimus	Torisel®	Pfizer
HSP90	HSP90	NVP-AUY922	–	Novartis
	HSP90	IPI-504	–	Infinity Pharmaceuticals
	HSP90	Ganetespib (STA-9090)	–	Synta Pharmaceuticals
	HSP90	AT13387^a	–	Astex Pharmaceuticals
	HSP90	BIIB021	–	Biogen Idec
HDAC	HDAC	Vorinostat (SAHA)	Zolinza®	Merck
	HDAC	Romidepsin (FK228, FR9011228)	Isodax®	Celgene
Proteasome	26S subunit	Bortezomib	Velcade®	Millennium Pharmaceuticals
Hedgehog	SMO	Vismodegib	Erivedge®	Genentech/Roche
CDK	CDK1/2/4/6/7	Alvocidib	Flavopiridol®	Tolero Pharmaceuticals
	CDK4/6	Palbociclib (PD-0332991)	–	Pfizer
CTLA	CTLA-4	Ipilimumab^b,^e,^f	Yervoy®	Bristol-Myers Squibb
DNA replication	Topoisomerase I	Irinotecan^e,^h	Camptosar®	Pfizer
	DNA (alkylation)	Temozolomide^h	Temodar®, Temodal®, Temcad®	Merck, Cadila Pharmaceuticals
	DNA (minor groove)	Brostallicin^h	–	Cell Therapeutics
DNA repair/DNA synthesis	DNA crosslinking	Carboplatin^e,^h	Paraplatin®	Bristol-Myers Squibb
	DNA crosslinking	Cisplatin^e,^h	Platin®	Cadila Healthcare
DNA synthesis	Thymidilate synthase	Floxuridine^h	FUDR®	Mayne Pharma
DNA backbone cleavage		Trabectedin (ecteinascidin 743)^h	Yondelis®	Zeltia
Tumor hypoxia		TH-302^b	–	Threshold Pharmaceuticals

Notes: Compounds currently in clinical trial for GIST, according to clinicaltrials.gov as of September 10, 2013.

a Also tested in combination with imatinib or sunitinib;

b only tested in combination with imatinib or sunitinib;

c only tested in combination with chemotherapy agents or radiation therapy;

d also tested in combination with other small molecule inhibitors;

e only tested in combination with other small molecule inhibitors;

f antibody;

g specifically tested on advanced GIST with the PDGFRA D842V mutation;

h chemotherapeutic agent.

Abbreviations: AKT, v-AKT murine thymoma viral oncogene homolog; BRAF, v-RAF murine sarcoma viral oncogene homolog B1; BCR-ABL, break point cluster region-Abelson; CDK, cyclin-dependent kinase; CSF-1R, colony stimulating factor 1 receptor; CTLA, cytotoxic lymphocyte-associated; DDR, discoidin domain receptor; EGFR, epidermal growth factor receptor; EPH, ephrin receptor; FGFR, fibroblast growth factor receptor; FLT, FMS-related tyrosine kinase 3; HDAC, histone deacetylase; HSP90, heat shock protein 90; IGFR, insulin-like growth factor receptor; IR, insulin receptor; KIT, kitten; LCK, lymphocyte-specific protein-tyrosine kinase; LYN, v-YES-1 Yamaguchi sarcoma viral related oncogene homolog; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; PI3K, phosphoinositide 3-kinase; RAF-1, v-RAF-1 murine leukemia viral oncogene homolog; RET, rearranged during transfection; SMO, smoothened; SRC, v-SRC avian sarcoma viral oncogene homolog; TIE, tyrosine kinase with immunoglobulin and EGF factor homology domains; VEGFR, vascular endothelial growth factor receptor; ZAK, leucine zipper- and sterile alpha motif-containing kinase.

Figure 1 Chemical structure of regorafenib and sorafenib. (A) Regorafenib (Stivarga^®). (B) Sorafenib (Nexavar^®). Note the difference of only one fluorine/carbon atom in the central phenyl ring (pink and arrows). Regorafenib is sometimes referred to as “fluoro-sorafenib”.