Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update

Abstract

Gastrointestinal stromal tumor (GIST) is characterized by well-defined oncogenes. Despite the significant improvement in treatment outcomes with adjuvant imatinib therapy for patients, drug resistance remains a major challenge for GIST therapy. This review focuses on the mechanisms contributing to drug resistance phenotype in GIST, such as primary imatinib-resistant mutants, secondary mutations, non-covalent binding of TKI to its target, tumor heterogeneity, re-activation of pro-survival/proliferation pathways through non-KIT/PDGFRA kinases, and loss of therapeutic targets in wild-type GIST. Corresponding suggestions are proposed to overcome drug-resistance phenotype of GIST. This review also summarizes the suitability of currently approved TKIs on different KIT/PDGFRA mutations and updates related clinical trials. Recent potent drugs and emerging strategies against advanced GISTs in clinical trials are presented. Additionally, metabolic intervention offers a new avenue for clinical management in GIST. A landscape of metabolism in GIST and metabolic changes under imatinib treatment are summarized based on currently published data. The OXPHOS pathway is a promising therapeutic target in combination with TKI against sensitive KIT/PDGFRA mutants. Comprehensive understanding of the above resistance mechanisms, experimental drugs/strategies and metabolic changes is critical to implement the proper therapy strategy and improve the clinical therapy outcomes for GIST.

Keywords: Drug resistance; GIST; Imatinib; Metabolism; Tyrosine kinase inhibitor.

Fig. 1

Molecular pathology of GIST. A. Schemes of inactivated and activated wild-type oncoprotein (KIT/PDGFRA). B. Mutation pattern of KIT/PDGFRA mutants. C. Mutations in wild-type GISTs.

Fig. 2

Drug resistance mechanisms in GIST cells with KIT/PDGFRA mutants, KIT as a model. A. Steric hindrance. Duplication in exon 9 induces TKD in an activation conformation, which prohibits entry of imatinib [15]. Deletion in exon 11 creates a TKD conformation, which permits imatinib entry. Double mutations in exon 11 (deletion) and exon 14 (T670I) create a TKD conformation which prohibit imatinib entry [30]. B. Enhanced affinity for ATP or enhanced catalytic velocity. Deletion in exon 11 creates a TKD conformation, which permits imatinib entry. Double mutation in exon 11 (deletion) and exon 13/14 (V654A, T670I) create a TKD conformation which could have enhanced affinity for ATP [15]. Double mutation in exon 11 (deletion) and exon 17 (activation loop) create a TKD conformation which could have enhanced catalytic velocity and affinity to ATP [15]. C. Leaky activation. Reversible binding of imatinib to catalytic center permits leaky entry of ATP and activation of KIT.

Fig. 3

Targeted therapy in GIST. A. Current approved adjuvant therapies for GIST. B. Emerging TKIs targeting MAPK/ERK, PI3K/AKT, mTORC1, and the cell cycle. C. Therapeutic antibodies targeting KIT. D. Antibody–drug conjugates for GIST therapy.

Fig. 4

Metabolism changes in GISTs. A. Metabolic changes in GISTs without imatinib treatment. B. Metabolic changes in GISTs under insufficient concentrations of imatinib. C. Metabolic changes in GISTs with sufficient concentrations of imatinib.