Related Experiment Video

Updated: Mar 8, 2026

Study of the DNA Damage Checkpoint using Xenopus Egg Extracts
10:55

Study of the DNA Damage Checkpoint using Xenopus Egg Extracts

Published on: November 5, 2012

17.2K

Ras-MEK Signaling Mediates a Critical Chk1-Dependent DNA Damage Response in Cancer Cells

Ho-June Lee1, Yi Cao2, Victoria Pham3

  • 1Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.

Molecular Cancer Therapeutics
|February 1, 2017
PubMed

Insights

Researchers discovered a new cancer vulnerability in the DNA damage response kinase Chk1, crucial for survival in certain ovarian, breast, and osteosarcoma cells. Targeting Chk1 shows promise for treating these cancers, irrespective of p53 status.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • The DNA damage response (DDR) is critical for maintaining genomic stability.
  • Checkpoint kinase 1 (Chk1) plays a key role in the DDR pathway.
  • Therapeutic targeting of Chk1 is explored, particularly in p53-deficient cancers.

Purpose of the Study:

  • To identify novel kinase dependencies in cancer cells.
  • To investigate the role of Chk1 in cancer cell survival upon DNA damage.
  • To explore the interplay between Ras-MEK signaling and Chk1 in cancer.

Main Methods:

  • Cancer cell line profiling to identify kinase dependencies.
  • Analysis of Chk1 expression and activity in response to DNA damage.
  • Investigating the effects of Chk1 inhibition in combination with genotoxic chemotherapy.

Main Results:

  • A novel, non-mutational dependency on Chk1 was identified in cancer cells.
  • Ras-MEK signaling promotes Chk1 expression and dependency, supporting cancer cell survival.
  • Chk1 regulates Ras-MEK signaling through a negative feedback loop.
  • Exogenous DNA damage enhances Chk1 dependency.
  • Pharmacologic Chk1 inhibition potentiates chemotherapy-induced tumor cell killing.

Conclusions:

  • Ras-MEK signaling creates a dependency on Chk1 for survival in a subset of cancers, independent of p53 status.
  • Chk1 inhibition represents a potential therapeutic strategy for cancers dependent on this pathway.
  • A diagnostic strategy can identify patients who may benefit from Chk1-targeted therapies.

More Related Videos

Visualization of DNA Repair Proteins Interaction by Immunofluorescence07:55

Visualization of DNA Repair Proteins Interaction by Immunofluorescence

Published on: June 26, 2020

11.3K
Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage10:44

Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage

Published on: January 31, 2018

10.8K

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
8.9K
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...
5.0K
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
10.3K
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
3.3K
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...
7.6K
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...
6.0K