Related Experiment Video

Updated: Jan 24, 2026

Isolation and Characterization of Extracellular Vesicles Produced by Iron-limited Mycobacteria
08:27

Isolation and Characterization of Extracellular Vesicles Produced by Iron-limited Mycobacteria

Published on: October 31, 2019

8.0K

KRASG12C inhibition produces a driver-limited state revealing collateral dependencies

Kevin Lou1, Veronica Steri2,3, Alex Y Ge2,4

  • 1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.

Science Signaling
|May 30, 2019
PubMed

Insights

Targeting KRAS G12C with new inhibitors shows promise for cancer treatment. Researchers identified "collateral dependencies" to enhance therapy effectiveness and block cancer cell survival.

Area of Science:

  • Oncology
  • Genomics
  • Pharmacology

Background:

  • KRAS G12C is a common oncogenic driver in various cancers.
  • KRAS G12C inhibitors offer a targeted therapeutic approach by binding to the mutant cysteine residue.
  • Understanding resistance mechanisms and dependencies is crucial for optimizing KRAS G12C inhibitor efficacy.

Purpose of the Study:

  • To systematically identify genetic interactions with KRAS G12C inhibitors using a CRISPR interference platform.
  • To discover genes that, when lost, sensitize cells to KRAS G12C inhibition, termed "collateral dependencies" (CDs).
  • To explore combination therapies targeting these CDs for enhanced anti-cancer effects.

Main Methods:

  • Utilized a genome-scale CRISPR interference (CRISPRi) functional genomics platform.
  • Screened cellular models of KRAS G12C-mutant lung and pancreatic cancer.
  • Identified genes essential in the KRAS G12C-inhibitor-treated state.

Main Results:

  • Discovered novel "collateral dependencies" (CDs) – genes whose loss enhances sensitivity to KRAS G12C inhibitors.
  • Identified two classes of combination therapies targeting CDs.
  • Demonstrated that targeting CDs can increase KRAS G12C target engagement and block residual survival pathways in vitro and in vivo.

Conclusions:

  • KRAS G12C inhibitors represent a significant advancement in oncogene-specific cancer therapy.
  • Collateral dependencies offer new targets for combination strategies to overcome treatment resistance.
  • A framework for assessing genetic dependencies induced by oncogene inhibition was proposed.

More Related Videos

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics04:01

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics

Published on: March 15, 2024

1.9K
Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres06:52

Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres

Published on: July 22, 2020

6.9K

Related Concept Videos

Limiting Reactant02:27

Limiting Reactant

The relative amounts of reactants and products represented in a balanced chemical equation are often referred to as stoichiometric amounts. However, in reality, the reactants are not always present in the stoichiometric amounts indicated by the balanced equation.
69.5K
Feedback Inhibition00:46

Feedback Inhibition

Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.0K
The Number e as a Limit01:29

The Number e as a Limit

The number e is a fundamental constant in calculus, playing a central role in describing continuous change, particularly exponential growth. It is most naturally defined through its relationship with the natural logarithm, which is the inverse of the exponential function with base e. This relationship allows e to be characterized using basic principles of differentiation rather than as an arbitrary numerical constant.A key property of the natural logarithm function, ln x, is that its derivative...
72
Sympathetic Pathways: Collateral Ganglia and Adrenal Medulla01:27

Sympathetic Pathways: Collateral Ganglia and Adrenal Medulla

The sympathetic pathways of the collateral ganglia and adrenal medulla serve unique but interconnected roles in the sympathetic response.
Collateral Ganglia
Sympathetic preganglionic axons reach the collateral ganglia along the route of splanchnic nerves. These nerves bypass the sympathetic trunk and communicate with sympathetic postganglionic neurons housed in the prevertebral ganglia. These ganglia supply the organs of the abdominopelvic cavity.
The greater splanchnic nerve, formed by the...
2.6K
Frequency-dependent Selection01:21

Frequency-dependent Selection

When the fitness of a trait is influenced by how common it is (i.e., its frequency) relative to different traits within a population, this is referred to as frequency-dependent selection. Frequency-dependent selection may occur between species or within a single species. This type of selection can either be positive—with more common phenotypes having higher fitness—or negative, with rarer phenotypes conferring increased fitness.
23.3K
Enzyme Inhibition01:30

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
91.8K