Related Experiment Video

Updated: Nov 2, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

15.0K

Systematic screening reveals synergistic interactions that overcome MAPK inhibitor resistance in cancer cells

Yu Yu1, Minzhen Tao2, Libin Xu3

  • 1Department of Cell Biology, Basic Medical College, Army Medical University (Third Military Medical University), Chongqing 400038, China.

Cancer Biology & Medicine
|June 9, 2021
PubMed
Abstract

Insights

New drug combinations targeting specific gene interactions can overcome resistance to MAPK inhibitor (MAPKi) cancer therapies. Researchers identified synergistic combinations like ITGB3 + IGF1R to suppress adaptive cancer stemness during MAPKi treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mitogen-activated protein kinase inhibitor (MAPKi) resistance is a significant challenge in cancer therapy.
  • Adjuvant therapeutic strategies are crucial to overcome this common resistance mechanism.

Purpose of the Study:

  • To systematically identify genetic interactions underlying MAPKi resistance.
  • To investigate mechanisms generating synergistic MAPKi resistance.

Main Methods:

  • Conducted pair-wise sgRNA-based high-throughput screening to identify synergistic interactions.
  • Validated combinations using growth, viability, and spheroid assays.
  • Analyzed clinical relevance via The Cancer Genome Atlas and immunohistochemistry.
  • Investigated resistance mechanisms using molecular assays (co-IP, Western blot, qRT-PCR, immunofluorescence).

Main Results:

  • Identified three novel synergistic combinations targeting MAPKi resistance: ITGB3 + IGF1R, ITGB3 + JNK, and HDGF + LGR5.
  • Discovered a novel HDGF-LGR5 protein complex that enhances cancer cell stemness in response to MAPKi.
  • Showed that ITGB3 + JNK or ITGB3 + IGF1R inhibitors modulate the HDGF-LGR5 complex.

Conclusions:

  • Pair-wise sgRNA screening offers systematic insights into MAPKi resistance.
  • ITGB3 + IGF1R targeting drugs (cilengitide + linsitinib) can suppress the HDGF-LGR5 complex.
  • This suppression inhibits cancer stemness, offering a potential therapeutic strategy against MAPKi resistance.
Keywords:
MAPKi resistancePair-wise sgRNA librarycancer stemnesscombinatorial therapygenetic interactions

More Related Videos

A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells05:29

A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells

Published on: March 28, 2021

3.0K
Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes08:32

Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes

Published on: May 23, 2025

710

Related Concept Videos

Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.3K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.8K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.0K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.5K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.1K