Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1-2% of gastrointestinal neoplasms. About 75-80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5-10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10-15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

Keywords: GIST; imatinib; immunotherapy; small molecules.

Figure 1

The role of the receptors in the activation of signaling pathways in GISTs. The four major receptors groups (RTKs, PDGFR, c-KIT, and VEGFR) closely regulate the cellular process such as angiogenesis, cell proliferation and motility, and anti-apoptotic capability of cancer cells through the induction of RAF/MEK/ERK, PI3K/AKT/mTOR, PKC, and Src/FAK axis. In addition, a plethora of small agents that directly target the receptors or signaling pathways is presented in the figure.