The GIST paradigm: lessons for other kinase-driven cancers

摘要

Gastrointestinal stromal tumour (GIST) is the most common sarcoma of the intestinal tract, known to be notoriously refractory to conventional chemotherapy or radiation. It is an ideal solid tumour model to apply our understanding from aberrant signal transduction to drug development, since nearly all tumours have a mutation in the KIT or, less often, the PDGFRA or BRAF genes. The constitutively activated KIT and PDGFRA oncoproteins serve as crucial diagnostic and therapeutic targets. The discovery of oncogenic KIT activation as a central mechanism of GIST pathogenesis suggested that inhibiting or blocking KIT signalling might be the milestone in the targeted therapy of GISTs. Indeed, imatinib mesylate inhibits KIT kinase activity and represents the front-line drug for the treatment of unresectable and advanced GISTs, achieving a partial response or stable disease in about 80% of patients with metastatic GIST. KIT mutation status has a significant impact on treatment response, emerging in recent years as a leading paradigm for genotype-driven targeted therapy. In this review, parallels with other models in oncology that share their addiction to a particular mutationally activated kinase are contrasted. A better understanding of oncogene addiction as a common theme across tumours of diverse histologies underlies the clinical success of targeting such kinases with several selective kinase inhibitors. Also remarkable is the similarity displayed in the mechanisms of drug failure after a successful but temporary clinical response to kinase inhibition. Reactivation of the same oncogenic kinase, often by acquisition of second site mutations, is another emerging paradigm of secondary resistance in these tumour models. The complexity of polyclonal resistance in imatinib-resistant patients argues that single next-generation kinase inhibitors will not be beneficial in all mutant clones. Other broad therapeutic strategies could include combination of kinase inhibitors with ta...