Dataset Information

Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor

ABSTRACT: AKT activation is a hallmark of IM resistance in GIST. The presence of an additional therapeutic agent could potentially suppress the growth and survival of a clone of cancer cells, which have developed resistance to IM. Simultaneous targeting of AKT in addition to inhibiting KIT with IM has potential to be a promising strategy to prevent the development of secondary resistance to IM. Our group has previously shown significantly enhanced combination effects of IM with MK-2206, an oral pan-AKT inhibitor, in an IM-sensitive xenograft model in vivo, as measured by extended disease stabilization and improved survival. In this study, we evaluated the efficacy of a new selective, allosteric pan-AKT inhibitor, ARQ 751 (Merck, ArQule) in both IM-sensitive and resistant GIST in vivo models, including a GIST patient-derived xenograft (PDX) possessing an exon 9 KIT mutation. We report superior activity of ARQ 751 in combination with IM in a panel of IM-sensitive and IM-resistant GIST cell lines in vitro. This activity is mediated by increased PDCD4 expression leading to increased apoptosis and cell cycle arrest. Furthermore, dual inhibition of KIT and AKT provided impressive diseases stabilization in IM-sensitive GIST xenografts and trends toward stabilization in IM-resistant models in vivo.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Lori Rink

PROVIDER: MSV000086739 | MassIVE | Wed Jan 20 23:27:00 GMT 2021

SECONDARY ACCESSION(S): PXD023717

REPOSITORIES: MassIVE

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Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor.

Kozinova Marya M Joshi Shalina S Ye Shuai S Belinsky Martin G MG Sharipova Dinara D Farma Jeffrey M JM Reddy Sanjay S SS Litwin Samuel S Devarajan Karthik K Campos Alex Rosa AR Yu Yi Y Schwartz Brian B von Mehren Margaret M Rink Lori L

Cancers 20210723 15

The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation. In addition to KIT, AKT is a relevant target for inhibition, since the PI3K/AKT pathway is crucial for IM-resistant GIST survival. We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell l ...[more]

PMID: 34359600

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