Molecular Mechanisms of Gastrointestinal Stromal Tumors and Their Impact on Systemic Therapy Decision

Abstract

Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that mostly derive from Cajal cell precursors. They are by far the most common soft tissue sarcomas. Clinically, they present as gastrointestinal malignancies, most often with bleeding, pain, or intestinal obstruction. They are identified using characteristic immunohistochemical staining for CD117 and DOG1. Improved understanding of the molecular biology of these tumors and identification of oncogenic drivers have altered the systemic treatment of primarily disseminated disease, which is becoming increasingly complex. Gain-of-function mutations in KIT or PDGFRA genes represent the driving mutations in more than 90% of all GISTs. These patients exhibit good responses to targeted therapy with tyrosine kinase inhibitors (TKIs). Gastrointestinal stromal tumors lacking the KIT/PDGFRA mutations, however, represent distinct clinico-pathological entities with diverse molecular mechanisms of oncogenesis. In these patients, therapy with TKIs is hardly ever as effective as for KIT/PDGFRA-mutated GISTs. This review provides an outline of current diagnostics aimed at identifying clinically relevant driver alterations and a comprehensive summary of current treatments with targeted therapies for patients with GISTs in both adjuvant and metastatic settings. The role of molecular testing and the selection of the optimal targeted therapy according to the identified oncogenic driver are reviewed and some future directions are proposed.

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

“…Notably, SNPs in the tested pharmacokinetic genes were not associated with a difference in PFS or OS, despite previous, sometimes conflicting, reports indicating otherwise ( 22 - 24 ). It is possible that most patients had IM trough concentrations higher than the threshold level required for clinical activity, negating any effects that these SNPs might have had on the actual serum concentrations above this level.…”

Multi-disciplinary management of recurrent gastrointestinal stromal tumor harboring KIT exon 11 mutation with the switch-control kinase inhibitor ripretinib and surgery`

“…For example, additional mutations in KIT and PDGFRA were detected post-treatment in patients with GIST progressing on TKI therapy [ 24 ]. The clonal evolution of cancer can be challenging particularly with multi-kinase inhibitors since it can lead to isolated subclonal progression in heterogenous tumor sites [ 25 – 28 ]. Such localized progression, as seen in our patient, can be managed through surgical resection of non-responding lesions [ 29 , 30 ].…”

Gastric Cancer Vascularization and the Contribution of Reactive Oxygen Species

“…The ones (5–7.5% of all GIST) with KIT/PDGFRA wild-types are then sub-classified depending on the functionality of the succinate dehydrogenase enzyme (SDH B/C/D), which might be deficient due to mutation or epigenetic regulation. In the rare cases when no KIT/PDGFRA mutations are detected and the SDH complex is functional, several very rare driver alterations could have occurred in genes such as the RAS gene family, BRAF, NF1, NTRK1–3, and FGFR1–4 [ 67 ]. To date, surgery is the only therapeutic option in combination with adjuvant chemotherapy based on the tyrosine kinase inhibitor (TKi) Imatinib mesylate for KIT/PDGFRA-mutated patients [ 68 ].…”