Novel approaches to imatinib- and sunitinib-resistant GIST.
Gastrointestinal stromal tumors (GISTs) generally arise from primary activating mutations in the KIT or PDGFRA genes that result in constitutive activation of receptor tyrosine kinase activity. Imatinib provides targeted therapy for GIST by inhibiting the KIT and PDGFR-alpha tyrosine kinases. Clinical benefit is achieved in approximately 85% of patients with unresectable or metastatic disease, with a median progression-free survival of 20 to 24 months. The mechanisms of acquired resistance to imatinib are heterogeneous, with most involving the emergence of secondary mutations in KIT exons 13, 14, or 17. In patients failing or intolerant to imatinib, the multitargeted agent sunitinib achieves durable disease control in approximately 50% of cases. Experimental treatment options beyond those currently available consist of other KIT-targeting tyrosine kinase inhibitors, such as nilotinib, or agents targeting alternative pathways, such as antiangiogenic agents, mammalian target of rapamycin, RAF kinase, and chaperone inhibitors.
Reichardt
Peter
P
Helios Klinikum Bad Saarow, Department of Hematology, Oncology, and Palliative Care, Sarcoma Center Berlin-Brandenburg, Pieskower Strasse 33, 15526 Bad Saarow, Germany. peter.reichardt@helios-kliniken.de
D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib
D020533:Angiogenesis Inhibitors; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib
Mol Cancer Ther. 2007 Mar;6(3):1159-66
17363509
J Clin Oncol. 2003 Dec 1;21(23):4342-9
14645423
Lancet. 2006 Oct 14;368(9544):1329-38
17046465
J Clin Oncol. 2006 Oct 10;24(29):4764-74
16954519
Gastroenterology. 2005 Feb;128(2):270-9
15685537
Cancer Res. 2006 Jan 1;66(1):473-81
16397263
Cancer Res. 2006 Sep 15;66(18):9153-61
16982758
J Clin Oncol. 2004 Sep 15;22(18):3813-25
15365079
J Clin Pathol. 2006 Jun;59(6):557-63
16731599
J Clin Oncol. 2008 Feb 1;26(4):626-32
18235122
Cancer Res. 2006 Jun 1;66(11):5858-66
16740725
N Engl J Med. 2002 Aug 15;347(7):472-80
12181401
Science. 1998 Jan 23;279(5350):577-80
9438854
Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34
15451219
Cancer Cell. 2005 Feb;7(2):129-41
15710326
Eur J Cancer. 2006 May;42(8):1093-103
16624552
Pharmacology. 2006;77(1):11-6
16534250
J Clin Oncol. 2008 Feb 1;26(4):620-5
18235121
Ann Oncol. 2008 Jan;19(1):173-7
17698976