Related Experiment Video

Updated: Jul 1, 2026

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
07:40

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions

Published on: May 27, 2021

Identification of a small molecule with synthetic lethality for K-ras and protein kinase C iota

Wei Guo1, Shuhong Wu, Jinsong Liu

  • 1Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Cancer Research
|September 17, 2008
PubMed

Insights

A new compound, oncrasin-1, effectively kills lung cancer cells with K-Ras mutations by inducing apoptosis. This targeted therapy shows promise for treating cancers resistant to current treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • K-Ras mutations are common in cancers and linked to poor prognosis and treatment resistance.
  • Overexpression of protein kinase C iota (PKCiota), activated by Ras, also correlates with poor cancer outcomes.
  • No effective treatments currently exist for cancers with K-Ras mutations or PKCiota overexpression.

Purpose of the Study:

  • To identify a novel therapeutic agent for cancers characterized by K-Ras mutations or PKCiota overexpression.
  • To investigate the mechanism of action of a newly identified compound, oncrasin-1.

Main Methods:

  • Synthetic lethality screening was employed to identify oncrasin-1.
  • In vitro assays assessed the cytotoxic effects of oncrasin-1 on lung cancer cells, including apoptosis induction and caspase activation.
  • siRNA was used to block K-Ras or PKCiota to confirm the drug's target pathway.
  • In vivo studies evaluated oncrasin-1's efficacy in suppressing human lung tumor xenografts in mice.

Main Results:

  • Oncracin-1 demonstrated potent cytotoxicity against human lung cancer cells with K-Ras mutations at low concentrations.
  • Cytotoxicity was mediated by apoptosis induction, evidenced by increased apoptotic cells and activated caspase-3 and caspase-8.
  • Oncracin-1 treatment caused abnormal nuclear aggregation of PKCiota in sensitive cells.
  • Apoptosis induction by oncrasin-1 was dependent on K-Ras and PKCiota, indicating a novel K-Ras/PKCiota pathway.
  • In vivo, oncrasin-1 significantly suppressed tumor growth (>70%) and prolonged survival in mice without detectable toxicity.

Conclusions:

  • Oncracin-1 is a potent inducer of apoptosis in K-Ras-mutant cancer cells.
  • The drug targets a novel K-Ras/PKCiota pathway, offering a new therapeutic strategy.
  • Oncracin-1 represents a promising new class of anticancer agents for K-Ras-driven cancers.

More Related Videos

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...