Mechanism of Resistance in Gastrointestinal Stromal Tumors

Imatinib has revolutionized the treatment of GIST since this drug is able to inhibit tumoral growth by blocking the activity of receptor tyrosine kinases, KIT or PDGFRA, that in these tumors are constitutively activated because of the presence of mutations that alters their catalytic activity. However, despite this enormous improvement in the RFS and OS and in the quality of life of GIST patients, imatinib is not able to eradicate the disease: recurrences occur and acquired resistance is a common event which develops during targeted treatments. Several mechanisms have been demonstrated to be responsible for tumoral growth reactivation which is due to the reactivation of the altered KIT/PDGFRA receptors, no more blocked by the drug. Secondary point mutations are generally observed in the regrowing tumors, and it has been demonstrated that they alter the architectural structure of the site in which the interaction between the drug and the receptor happens. Other mechanisms causing drug resistance have been investigated, indicating that many aspects need to be still explicated and fully understood in order to define a strategy able to fight definitively GIST growth.