Targeting Disease Persistence in Gastrointestinal Stromal Tumors

Abstract

SummaryGastrointestinal stromal tumors (GISTs) represent 20%-40% of human sarcomas. Although approximately half of GISTs are cured by surgery, prognosis of advanced disease used to be poor due to the high resistance of these tumors to conventional chemo- and radiotherapy. The introduction of molecularly targeted therapy (e.g., with imatinib mesylate) following the discovery of the role of oncogenic mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor α (PDGFRA) significantly increased patient survival. However, GIST cells persist in 95%-97% of imatinib-treated patients who eventually progress and die of the disease because of the emergence of clones with drug-resistant mutations. Because these secondary mutations are highly heterogeneous, even second- and third-line drugs that are effective against certain genotypes have only moderately increased progression-free survival. Consequently, alternative strategies such as targeting molecular mechanisms underlying disease persistence should be considered. We reviewed recently discovered cell-autonomous and microenvironmental mechanisms that could promote the survival of GIST cells in the presence of tyrosine kinase inhibitor therapy. We particularly focused on the potential role of adult precursors for interstitial cells of Cajal (ICCs), the normal counterpart of GISTs. ICC precursors share phenotypic characteristics with cells that emerge in a subset of patients treated with imatinib and in young patients with GIST characterized by loss of succinate dehydrogenase complex proteins and lack of KIT or PDGFRA mutations. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to tumor genotype and phenotype.

Significance: Gastrointestinal stromal tumors (GISTs) are one of the most common connective tissue cancers. Most GISTs that cannot be cured by surgery respond to molecularly targeted therapy (e.g., with imatinib); however, tumor cells persist in almost all patients and eventually acquire drug-resistant mutations. Several mechanisms contribute to the survival of GIST cells in the presence of imatinib, including the activation of "escape" mechanisms and the selection of stem-like cells that are not dependent on the expression of the drug targets for survival. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to the genetic makeup and other characteristics of the tumors.

Figure 1.

Hypothetical stem cell model of GIST persistence and acquired therapy resistance. Light blue circles: KIT-independent precursor cells carrying imatinib-sensitive KIT mutation but expressing very little or no KIT protein (KIT^low/−). Dark blue circles: KIT⁺ cells arising from the KIT^low/− cells carrying imatinib-sensitive KIT mutation. Open circles: dead cells. Pink circles: KIT^low/−, KIT-independent precursors with acquired secondary imatinib-resistant mutation. Red circles: KIT⁺ cells differentiated from the KIT^low/− precursors with secondary imatinib-resistant mutation. Filled arrow: imatinib treatment. Open arrow: cessation of imatinib treatment. Abbreviations: GIST, gastrointestinal stromal tumor; KIT^lo/−, cells with low or no expression of KIT; KIT⁺, cells expressing KIT.

Figure 2.

Mechanisms of disease persistence in GIST. Green and gray boxes signify cell-autonomous and microenvironmental mechanisms, respectively. The depicted mechanisms are not mutually exclusive. Abbreviations: GIST, gastrointestinal stromal tumor; WT, wild type.