Mechanisms of secondary resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumours (Review).
Treatment of patients affected by advanced or inoperable GIST was revolutionized by the use of the tyrosine kinase inhibitors. Despite the fact that most patients have a good durable response of disease, they develop a resistance to treatments after a median time of 24 months. The acquired resistance is an emerging aspect in medical oncology especially in the era of target therapies. The aim of this review is to report all known mechanisms of secondary resistance to tyrosine kinase inhibitors and to highlight their clinical implications. In general, they may be divided in mechanisms related to the acquisition of new molecular abnormalities associated to KIT and PDGFRA receptor signalling pathway, such as the loss of KIT expression, the genomic amplification of KIT, the activation of an alternative downstream signalling pathways such as AKT/mTOR and the acquisition of new receptor mutations, and other mechanisms different to KIT/PDGFRA receptors. Future research perspectives on target therapy and early resistance evaluation are also discussed.
Maleddu
Alessandra
A
Institute of Hematology and Medical Oncology 'L&A Seràgnoli', Sant'Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy. alessandramaleddu@gmail.com
Pantaleo
Maria A
MA
Nannini
Margherita
M
Di Battista
Monica
M
Saponara
Maristella
M
Lolli
Cristian
C
Biasco
Guido
G
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D017211:Treatment Failure
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha