Related Experiment Video

Updated: Feb 15, 2026

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

15.3K

Wee1 inhibitor MK1775 sensitizes KRAS mutated NSCLC cells to sorafenib

Elisa Caiola1, Roberta Frapolli2, Michele Tomanelli1

  • 1Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.

Scientific Reports
|January 19, 2018
PubMed

Insights

We found that KRAS-mutated Non-Small-Cell Lung Cancer (NSCLC) cells show resistance to sorafenib. Combining sorafenib with a Wee1 inhibitor, MK1775, can restore sensitivity in these resistant KRAS-mutated NSCLC models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Non-Small-Cell Lung Cancer (NSCLC) exhibits poor chemosensitivity, with targeted therapies limited to specific mutations (EGFR, ALK, ROS).
  • KRAS mutations are frequent in NSCLC, but patients with these mutations lack effective targeted treatments.
  • Sorafenib, a multi-kinase inhibitor, showed inconclusive results in clinical trials for KRAS-mutated NSCLC.

Purpose of the Study:

  • To investigate the differential response of KRAS-mutated NSCLC cells to sorafenib.
  • To identify novel therapeutic strategies to overcome sorafenib resistance in KRAS-mutated NSCLC.
  • To evaluate the efficacy of combining a Wee1 inhibitor with sorafenib.

Main Methods:

  • Assessed in vitro and in vivo response of KRAS G12V mutated NSCLC cells to sorafenib compared to wild-type.
  • Utilized high-throughput screening of a siRNA library targeting 719 kinases to identify resistance modulators.
  • Investigated the combination therapy of sorafenib with the Wee1 inhibitor MK1775.

Main Results:

  • KRAS G12V mutated NSCLC cells demonstrated reduced sensitivity to sorafenib compared to wild-type cells.
  • Wee1 was identified as a key modulator of sorafenib response in NSCLC cells.
  • Combination of Wee1 inhibition (MK1775) with sorafenib restored sensitivity in KRAS-mutated NSCLC cells.

Conclusions:

  • The response of NSCLC to sorafenib is dependent on the specific KRAS mutation type.
  • Wee1 inhibition represents a potential strategy to enhance sorafenib efficacy in KRAS-mutated NSCLC.
  • Further investigation of this combination therapy in diverse genetic backgrounds is warranted for KRAS-mutated NSCLC treatment.

More Related Videos

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids08:52

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Published on: November 22, 2021

4.7K
Exosomal miRNA Analysis in Non-small Cell Lung Cancer NSCLC Patients' Plasma Through qPCR: A Feasible Liquid Biopsy Tool08:49

Exosomal miRNA Analysis in Non-small Cell Lung Cancer NSCLC Patients' Plasma Through qPCR: A Feasible Liquid Biopsy Tool

Published on: May 27, 2016

11.7K

Related Concept Videos

Mutations01:39

Mutations

Overview
94.7K
Mutations01:35

Mutations

Mutations are changes in the sequence of DNA. These changes can occur spontaneously or they can be induced by exposure to environmental factors. Mutations can be characterized in a number of different ways: whether and how they alter the amino acid sequence of the protein, whether they occur over a small or large area of DNA, and whether they occur in somatic cells or germline cells.
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
44.7K
Viral Mutations00:36

Viral Mutations

A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
40.0K
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
11.1K
Mutation, Gene Flow, and Genetic Drift01:09

Mutation, Gene Flow, and Genetic Drift

In a population that is not at Hardy-Weinberg equilibrium, the frequency of alleles changes over time. Therefore, any deviations from the five conditions of Hardy-Weinberg equilibrium can alter the genetic variation of a given population. Conditions that change the genetic variability of a population include mutations, natural selection, non-random mating, gene flow, and genetic drift (small population size).
64.7K
Cancers Originate from Somatic Mutations in a Single Cell02:21

Cancers Originate from Somatic Mutations in a Single Cell

Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
15.0K