The combination of imatinib mesylate (IM), a KIT inhibitor, with an AKT inhibitor (MK-4440) showed promising results in stabilizing gastrointestinal stromal tumors (GISTs), a study published in the journal Cancers concluded.
“Dual inhibition of KIT and AKT provide impressive disease stabilization in IM-sensitive GIST xenografts and trends toward stabilization in IM-resistant models in vivo,” the authors stated.
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MK-4440, a novel pan-AKT allosteric inhibitor, and IM were tested in 3 GIST cell lines mimicking IM-sensitive and IM-resistant stages both as single agents and in combination. Kozinova et al found that the MK-4440/IM combined treatment promoted cell cycle arrest and unregulated the expression of programmed cell death 4 (PDCD4), leading to increased cell death.
In addition, the MK-4440/IM combination was administered to cell line- and GIST patient-derived xenografts. IM-sensitive xenografts showed greater disease stabilization and even tumor regression, in some cases, compared to the standard treatment. Despite the similar trend observed for IM-resistant xenografts, results did not reach significance.
IM (Gleevec®) is a first-line KIT inhibitor. KIT is frequently affected by oncogenic mutations in GIST and is a key player in GIST pathogenesis. With disease progression, most patients develop resistance to IM treatment due to the acquisition of secondary mutations in KIT or alterations in cell signaling.
Reference
Kozinova M, Joshi S, Ye S, et al. Combined inhibition of AKT and KIT restores expression of programmed cell death 4 (PDCD4) in gastrointestinal stromal tumor. Cancers (Basel). 2021;13(15):3699. doi:10.3390/cancers13153699
