A recent study published in Oncotarget, discussed the potential role of the kinase, ABL1 as a potential impediment to anti-tumor processes in GIST treated with imatinib mesylate.
The Life Raft Group’s Research Team member, Anette Duensing at the University of Pittsburgh School of Medicine, Department of Pathology, worked with collaborators to critically analyze the roles of two kinases present in GIST that may have an impact in therapeutic response.
Imatinib mesylate (Gleevec) is a pharmaceutical intervention that targets the KIT receptor tyrosine kinase. Tyrosine kinase is an enzyme that functions as an “on/off” switch for cellular functions. When protein kinases become mutated, they become stuck in the “on” position, thereby creating unregulated growth of the cell, which is necessary for the development of cancer. But imatinib was initially developed to target another kinase, ABL1, which is activated more specifically in patients with CML. (Chronic Myeloid Leukemia).
The study mentioned above demonstrated that ABL1 is also expressed along with KIT in the majority of gastrointestinal stromal tumors (GISTs). While this finding may be thought of as an added inhibitory benefit of imatinib, the concomitant inhibition of KIT and ABL1 in GIST may have an opposite effect. It led to reduced apoptosis (cell death) and a weakened inhibition of cell proliferation thus impeding the anti-tumor effect of sole KIT inhibition.
The role of the AKT S473 survival signaling, and how it promotes cell survival and growth, was explored in this study and also provided the explanation for the canceling out the therapeutic effect of imatinib.
While 85% of patients who are positive for a KIT mutation benefit from imatinib therapy, approximately 50% of patients with metatstatic or inoperable GIST show disease progression within the first two years of treatment (Hirota, et.al, 1998; Verweij, et.al, 2004).
The theory from the study indicates the importance of developing more effective therapies for GIST that do not also target ABL1 along with KIT. This opens up areas of investigation for future targeted treatments that may impede resistance.
The full study can be accessed here.
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279:577–80.
Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn, P. C., van Glabbeke M, Bertulli R, Judson I. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004; 364:1127–34.