ABSTRACT

Introduction ............................................................................................................ 128 KIT Gene and the KIT Protein ............................................................................... 129

KIT Mutants ...................................................................................................... 130 Mutations of KIT in GIST................................................................................. 132 Multiple Secondary Mutations of KIT in Resistant GIST ................................ 132 Mutations of KIT in Melanoma, Thymic Carcinoma, and Germ Cell Tumors ................................................................................... 132 Mutations of KIT in Hematological Malignancies ........................................... 133 Abnormal Trafficking of KIT Receptor Mutants .............................................. 134

Tyrosine Kinase Inhibitors of KIT ......................................................................... 134 Imatinib ............................................................................................................. 135 Sunitinib ............................................................................................................ 135 Other KIT Inhibitors ......................................................................................... 136

Nilotinib ....................................................................................................... 136 Masitinib ....................................................................................................... 136 Dasatinib ....................................................................................................... 136 Ponatinib ....................................................................................................... 136

Other Kinase Inhibitors Targeting Both KIT and VEGFR2 .............................. 136 Regorafenib .................................................................................................. 136 Sorafenib ...................................................................................................... 137 Pazopanib ..................................................................................................... 137 Dovitinib ....................................................................................................... 137 Motesanib ..................................................................................................... 137 Valatinib ....................................................................................................... 137

The KIT gene is mutated in several hematological malignancies and solid tumors in humans. The identification of the specific genetic alterations in the KIT gene (translocations, deletions, point mutations, amplifications) enables now to distinguish specific nosological groups within tumor types (gastrointestinal stromal tumor [GIST], melanoma, thymic carcinoma). Beyond the identification of these mutations as diagnostic tools, the nature of these driver mutations in tyrosine kinases enables to guide the administration of inhibitors of KIT, such as imatinib, sunitinib, and others in clinical setting. GIST, melanoma, and rare subsets of thymic carcinomas are known to be sensitive to these targeted therapies in advanced stage. Adjuvant treatment was found to improve survival in GIST patients with high risk of relapse. Yet, the emergence of multiclonal secondary resistance mutations encoding for a resistant form of the receptor within tumor cell masses remains a therapeutic challenge in advanced stage. The role of KIT inhibitors in other diseases in which no such mutations have been identified, such as aggressive fibromatosis (AF) or cystic adenoid carcinomas where a contribution of KIT is suspected, is unclear. The D816 mutations observed in mastocytosis, leukemia, and germ cell tumors result in intrinsic resistance to most tyrosine kinase inhibitors (TKIs) and represent a therapeutic challenge. Clinical research must include translational research programs to evaluate the response of the molecular target in vivo in the clinical setting and the mechanisms of resistance.