Related Experiment Video

Updated: Oct 29, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
07:08

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

Published on: January 16, 2020

5.8K

Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells

Wei-Ching Chen1, Minh D To1, Peter M K Westcott1,2

  • 1UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

Nature Communications
|July 14, 2021
PubMed

Insights

Coordinated splicing of KRAS4A and KRAS4B proteins is crucial for Kras mutant tumor development. Targeting KRAS4A splicing with drugs like Indisulam inhibits cancer stem cells, suggesting KRAS4A levels as a biomarker for therapeutic sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The KRAS oncogene produces two protein isoforms, KRAS4A and KRAS4B, through alternative splicing.
  • Aberrant KRAS signaling is a key driver in many human cancers, particularly pancreatic, colorectal, and lung cancers.
  • Understanding the distinct roles and regulation of KRAS isoforms is critical for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the coordinated regulation of KRAS4A and KRAS4B splicing in Kras mutant tumor development.
  • To elucidate the role of the KRAS4A isoform in cancer stem-like cells and its response to microenvironmental cues like hypoxia.
  • To identify therapeutic strategies targeting KRAS4A splicing and its impact on cancer stem cell viability.

Main Methods:

  • Differential splicing analysis of KRAS oncogene transcripts.
  • Investigation of KRAS4A and KRAS4B isoform expression under hypoxic and ER stress conditions.
  • Functional studies involving genetic deletion of KRAS4A and pharmacological inhibition of the DCAF15/RBM39 pathway using Indisulam.
  • Assessment of cancer stem cell populations and tumor growth inhibition.

Main Results:

  • Coordinated regulation of KRAS4A and KRAS4B splicing is essential for Kras mutant tumor formation.
  • The KRAS4A isoform is preferentially expressed in cancer stem-like cells and responds to hypoxia.
  • The KRAS4B isoform is induced by endoplasmic reticulum (ER) stress.
  • The DCAF15/RBM39 pathway controls KRAS4A splicing; its inhibition via Indisulam reduces cancer stem cells.
  • Deletion of KRAS4A also inhibits cancer stem cell activity.

Conclusions:

  • Targeting KRAS4A splicing represents a novel therapeutic strategy against Kras-driven cancers.
  • The minor KRAS4A isoform's levels in human tumors may serve as a predictive biomarker for sensitivity to therapies targeting KRAS4A splicing.
  • Existing drugs like Indisulam show potential for treating cancers driven by specific KRAS splicing patterns.

More Related Videos

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells07:23

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells

Published on: May 30, 2025

793
Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

18.2K

Related Concept Videos

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
Cancer Stem Cells and Tumor Maintenance02:40

Cancer Stem Cells and Tumor Maintenance

Early diagnosis and treatment can often cure cancer. However, even with treatment, residual cells called cancer stem cells (CSC) might remain, often causing tumor recurrence. These cancer stem cells possess the potential for self-renewal and multi-lineage differentiation and are often responsible for the therapeutic resistance displayed in most cancers.
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
5.1K
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...
6.6K
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
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.8K
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.3K