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

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

  • Cancers (Basel). 2021 Jul 23;13(15):3699. doi: 10.3390/cancers13153699.
Marya Kozinova 1 2,  Shalina Joshi 1,  Shuai Ye 1,  Martin G Belinsky 1,  Dinara Sharipova 1,  Jeffrey M Farma 3,  Sanjay S Reddy 3,  Samuel Litwin 4,  Karthik Devarajan 4,  Alex Rosa Campos 5,  Yi Yu 6,  Brian Schwartz 6,  Margaret von Mehren 1 7,  Lori Rink 1
Affiliations

Affiliations

  • 1 Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 2 Department of Molecular Pharmacology and Radiobiology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
  • 3 Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 4 Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • 5 Proteomics Core Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 6 ArQuIe Inc., A Wholly-Owned Subsidiary of Merck & Co., Inc. (Known as MSD Outside the United States and Canada), Kenilworth, NJ 07033, USA.
  • 7 Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
PMID: 34359600 DOI: 10.3390/cancers13153699
Abstract

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 lines and preclinical models with varying IM sensitivities. Dual inhibition of KIT and Akt demonstrated synergistic effects in IM-sensitive and -resistant GIST cell lines. Proteomic analyses revealed upregulation of the tumor suppressor, PDCD4, in combination treated cells. Enhanced PDCD4 expression correlated to increased cell death. In vivo studies revealed superior efficacy of MK-4440/IM combination in an IM-sensitive preclinical model of GIST compared with either single agent. The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of Akt inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with Akt inhibition in the resistant setting.

Keywords

AKT; GIST; PDCD4; gastrointestinal stromal tumor; imatinib mesylate.

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