Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor

Abstract

Small molecule kinase inhibitors have irrevocably altered cancer treatment. March 2010 marks the 10th anniversary of using imatinib in gastrointestinal stromal tumors (GIST), a cardinal example of the utility of such targeted therapy in a solid tumor. Before imatinib, metastatic GIST was frustrating to treat due to its resistance to standard cytotoxic chemotherapy. Median survival for patients with metastatic GIST improved from 19 to 60 months with imatinib. In treating patients with GIST, two patterns of tyrosine kinase inhibitor resistance have been observed. In the first, ~9–14% of patients have progression within 3 months of starting imatinib. These patients are classified as having primary or early resistance. Median progression-free survival (PFS) on imatinib is approximately 24 months; patients with later progression are classified as having secondary or acquired resistance. Primary studies and a meta-analysis of studies of imatinib in GIST patients have identified prognostic features that contribute to treatment failure. One of the strongest predictors for success of therapy is KIT or PDGFRA mutational status. Patients with KIT exon 11 mutant GIST have better response rates, PFS, and overall survival compared to other mutations. A great deal has been learned in the last decade about sensitivity and resistance of GIST to imatinib; however, many unanswered questions remain about secondary resistance mechanisms and clinical management in the third- and fourth-line setting. This review will discuss the role of dose effects, and early and late resistance to imatinib and their clinical implications. Patients intolerant to imatinib (5%) and those who progress on imatinib are treated with sunitinib. The mechanism of resistance to sunitinib is unknown at this time but is also appears related to growth of clones with secondary mutations in KIT. Third- and fourth-line treatments of GIST and with future treatment strategies are also discussed.

Sunitinib inhibits tumor vascularity and growth but does not affect Akt and ERK phosphorylation in xenograft tumors

“…Resistance did not appear in these models, suggesting that the anti-angiogenic action mediated by the block of phosphorylation of VEGF-R and PDGF-R is effective against well-established tumor types. In contrast, a considerable group of patients with RCC or GIST do not respond to this drug or eventually develop resistance to sunitinib therapy (6,7). At present the molecular mechanism underlying such a resistance are not fully clarified.…”

“…In patients with objective response to sunitinib, an early increase in VEGF serum levels with a decrease of VEGFR-2 (in RCC) or VEGFR-2 and 3 levels (in GIST) has been reported and interpreted as the result of hypo-oxigenation of the tumor mass (7,3). Their assessment in patients subjected to sunitinib treatment has been therefore proposed as biomarkers of its efficacy.…”

“…Similarly, in GIST resistant to imatinib, the treatment with sunitinib may also result in a secondary TK inhibitor resistance (7). Up-regulation of alternative kinase pathway has been proposed as one of the mechanisms of resistance to kinase inhibitors developing in tumor cells (8,9).…”

The G-quadruplex ligand, SYUIQ-FM05, targets proto-oncogene c-kittranscription and induces apoptosis in K562 cells

“…Imatinib mesylate suppresses c-Kit receptor phosphorylation and induces cancer cell apoptosis (Dolci et al, 2001;Chu et al, 2004;Lasater et al, 2008). RTKs are the current primary targets of cancer chemotherapies, but the emergence of drug resistance has urged the development of novel inhibitors of c-kit function (Al-Obeidi & Lam, 2000;Gounder & Maki, 2011;Kee & Zalcberg, 2012). The suppression of c-kit transcription using flavopiridol induces apoptosis in gastrointestinal stromal tumor cells through the inhibition of poly(ADP-ribose) polymerase and downstream ERK phosphorylation (Sambol et al, 2006).…”

PI3 kinase is indispensable for oncogenic transformation by the V560D mutant of c-Kit in a kinase-independent manner

“…The exon 11 mutation V560D of c-Kit is frequently identified in GISTs [10] while the exon 17 mutation D816V of c-Kit is frequently identified in mastocytosis and less frequently in certain types of AML [1]. In order to compare the transforming ability of these two types of mutants, we In order to investigate the mechanism behind the weak transforming ability of c-Kit/V560D, cKit activation was compared between wild-type c-Kit, c-Kit/V560D and c-Kit/D816V expressing cells.…”