Targeted therapy and personalized medicine in gastrointestinal stromal tumors: drug resistance, mechanisms, and treatment strategies

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Since the discovery that the KIT and PDGFRA receptor tyrosine kinases are the primary oncogenic drivers in the vast majority of GISTs, targeted therapy with tyrosine kinase inhibitors has been the mainstay of treatment for this disease. Using molecular profiling of tumor specimens, researchers also discovered that KIT and PDGFRA mutations are non-random and occur in specific regions of the receptors, and furthermore, that particular genotypes predicted response or resistance to targeted therapy. Imatinib, the first tyrosine kinase inhibitor used to treat GIST, remains the first-line therapy in advanced GIST and the only therapy confirmed through clinical trials in the adjuvant or neoadjuvant setting for resectable disease. Resistance to imatinib is well described and is either primary or secondary. Primary resistance is associated with specific tumor genotypes, so genotyping of individual patient tumors helps guide decision-making into whether to offer imatinib and at what dose. Secondary resistance occurs due to the acquisition of secondary mutations during therapy. Currently, the main strategy to combat imatinib resistance is to switch to another tyrosine kinase inhibitor, because imatinib-resistant GIST is usually still oncogenically addicted to KIT/PDGFRA signaling. Surgery can also be used to combat resistant disease in select settings. Unfortunately, progression-free and overall survival remains dismal for patients who develop imatinib-resistant disease, and further research into alternative strategies is still needed.

Keywords: GIST; imatinib; targeted therapy; tyrosine kinase inhibitor.

Figure 1

KIT and PDGFRA downstream signaling pathways. Abbreviations: SCF, stem cell factor; PDGF, platelet-derived growth factor, JNK, c-Jun N-terminal kinase; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; MEK, mitogen-activated protein kinase; MAPK, mitogen-activated protein kinase.

Figure 2

Location and frequency of primary mutations in KIT and PDGFRA.

Figure 3

Treatment algorithm for patients with resectable gastrointestinal stromal tumor (GIST) and mutational profiling. Notes: *High-risk features include: tumor rupture; mitotic rate >10 per 50 high-powered fields (HPF); diameter >10 cm; mitotic rate >5/50 HPF and diameter >5 cm; mitotic rate >5/50 HPF and diameter >2 cm and non-gastric GIST; diameter >5 cm and non-gastric GIST.

Figure 4

Treatment algorithm for patients with unresectable or metastatic GIST and mutational profiling. Abbreviations: TKI, tyrosine kinase inhibitor; GIST, gastrointestinal stromal tumor.