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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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K-Ras4B/calmodulin/PI3Kα: A promising new adenocarcinoma-specific drug target?

Ruth Nussinov1,2, Serena Muratcioglu3, Chung-Jung Tsai1

  • 1a Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , National Cancer Institute at Frederick , Frederick , MD , USA.

Expert Opinion on Therapeutic Targets
|February 14, 2016
PubMed
Abstract

Insights

A novel drug concept targets the K-Ras4B/Calmodulin/PI3Kα complex in cancers. This approach may overcome challenges in developing effective KRAS-targeted therapies, with potential for combination strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS-driven cancers (pancreatic, colorectal, lung) lack effective targeted therapies, especially for the KRAS4B splice variant.
  • Challenges include K-Ras4B's smooth surface, cancer heterogeneity, and drug toxicity.

Purpose of the Study:

  • To propose a novel adenocarcinoma-specific drug concept targeting K-Ras4B.
  • To explore the therapeutic potential of targeting the K-Ras4B/Calmodulin/PI3Kα complex.

Main Methods:

  • Focus on Calmodulin (CaM) binding specifically to K-Ras4B, unlike H-Ras or N-Ras.
  • Investigate CaM/Ca(2+) role in activating PI3Kα in cancer, potentially replacing RTK signaling.

Main Results:

  • Experimental and clinical data support the existence of an oncogenic GTP-bound K-Ras4B/CaM/PI3Kα complex.
  • High-resolution structural data (EM, crystal structure) could enable drug discovery targeting the CaM/PI3Kα interface.

Conclusions:

  • Targeting the K-Ras4B/CaM/PI3Kα complex addresses a critical unmet therapeutic need in KRAS-driven cancers.
  • Combination therapies, including those targeting cell-cycle control, may be necessary to overcome expected drug resistance.
Keywords:
K-Ras dimersKRASKRAS4AKRAS4Ballosteric drugscalciumcalmodulincolorectal cancerlung cancerorthosteric drugspancreatic cancerpancreatic ductal adenocarcinomas (PDAC)small molecule drug

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