Emerging Targeted Therapeutic Strategies to Overcome Imatinib Resistance of Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal neoplasms of the gastrointestinal tract. The gold standard for the diagnosis of GISTs is morphologic analysis with an immunohistochemical evaluation plus genomic profiling to assess the mutational status of lesions. The majority of GISTs are driven by gain-of-function mutations in the proto-oncogene c-KIT encoding the tyrosine kinase receptor (TKR) known as KIT and in the platelet-derived growth factor-alpha receptor (PDGFRA) genes. Approved therapeutics are orally available as tyrosine kinase inhibitors (TKIs) targeting KIT and/or PDGFRA oncogenic activation. Among these, imatinib has changed the management of patients with unresectable or metastatic GISTs, improving their survival time and delaying disease progression. Nevertheless, the majority of patients with GISTs experience disease progression after 2–3 years of imatinib therapy due to the development of secondary KIT mutations. Today, based on the identification of new driving oncogenic mutations, targeted therapy and precision medicine are regarded as the new frontiers for GISTs. This article reviews the most important mutations in GISTs and highlights their importance in the current understanding and treatment options of GISTs, with an emphasis on the most recent clinical trials.

Genomic profiling in GIST: Implications in clinical outcome and future challenges

“…The mutations are described in exon 12 (1 %) which codifies a portion of the JM domain of the protein, in exon 14 (<1 %) coding ATP binding domain, and in exon 18 (5 %) which comprises the activation loop. All these mutations cause constitutive activation of PDGFRA in the absence of ligand binding [19] . Similar to KIT mutations, PDGFRA mutations can activate a number of signal transduction molecules, including MAPK, AKT, STAT1, and STAT3 [16] .…”

“…This resistance is driven by secondary mutations or genomic amplifications of KIT/PDGFRA genes that lead to alterations in the kinase domain of the receptor to trigger the oncogenes activation. KIT secondary mutations are non-randomly distributed single nucleotide substitutions in 2 regions: (1) The encoded by exons 13 and 14 that codify ATP-interaction pocket and interfere with the TKI binding; (2) Mutations in exon 17 induce the stabilization of KIT in the active conformation and thus preclude TKI interaction [19] . These SR-KIT mutations are found in 50–67 % of patients with secondary imatinib-resistant.…”

“…These SR-KIT mutations are found in 50–67 % of patients with secondary imatinib-resistant. Therefore, the monitoring of them during treatment is essential to make timely decisions about therapeutic options in GIST [19] . Fig.…”

Contribution of genetic polymorphism in ABCB1 to individual variations of imatinib plasma levels in patients with gastrointestinal stromal tumor

“…Gastrointestinal stromal tumors (GISTs) originate from the interstitial cells of Cajal and represent the most common mesenchymal malignancy of the gastrointestinal tract ( 1 ). Somatic mutations in the KIT or platelet-derived growth factor receptor alpha ( PDGFRA ) genes resulting in activation of the oncogenic tyrosine kinases play a crucial role in GIST tumorigenesis ( 2 , 3 ). Imatinib mesylate (IM), a multitargeted tyrosine kinase inhibitor (TKI), binds to the adenosine triphosphate (ATP)-binding pocket of the KIT/PDGFRA kinase domain, competitively inhibiting substrate phosphorylation and suppressing cellular proliferation ( 4 ).…”