Related Experiment Video

Updated: Sep 10, 2025

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
09:29

Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies

Published on: September 30, 2016

13.9K

The RASAL2 variant promotes aberrant RAS signaling and resistance to anti-EGFR therapy in colorectal cancer

Yu-Min Yeh1, Yi-Hsuan Hsu2, Yi-Ting Huang2

  • 1Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Scientific Reports
|August 23, 2025
PubMed

Insights

A rare RASAL2 gene variant (c.2423 A>G) increases colorectal cancer (CRC) risk and promotes resistance to anti-EGFR therapy by enhancing RAS signaling. This finding may aid in predicting CRC progression and treatment response.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Metastatic colorectal cancer (CRC) treatment relies on anti-EGFR antibodies, but resistance is a significant challenge in KRAS/NRAS/BRAF wild-type patients.
  • RASAL2 (RAS protein activator-like 2) is a regulator of RAS signaling, crucial for cellular processes.
  • Identifying genetic factors influencing CRC progression and therapy resistance is vital for improving patient outcomes.

Purpose of the Study:

  • To investigate the pathogenicity of the germline RASAL2 c.2423 A>G variant.
  • To determine the role of this variant in colorectal cancer (CRC) development and resistance to anti-EGFR therapy.
  • To evaluate RASAL2 c.2423 A>G as a potential biomarker for CRC risk and therapeutic response.

Main Methods:

  • Population frequency analysis of the RASAL2 c.2423 A>G variant in East Asian and Taiwanese CRC patient cohorts.
  • Functional assays to assess the impact of the RASAL2 c.2423 A>G variant on RAS signaling pathways (ERK phosphorylation).
  • In vitro studies evaluating the effect of the variant on CRC cell proliferation and response to cetuximab (anti-EGFR therapy).
  • Classification of the variant's pathogenicity using the American College of Medical Genetics and Genomics (ACMG) criteria.

Main Results:

  • The RASAL2 c.2423 A>G variant is rare in East Asians (0.01%) but more prevalent in Taiwanese CRC patients (1.63%).
  • The variant enhances RAS signaling, leading to sustained ERK phosphorylation and increased CRC cell proliferation.
  • RASAL2-mutant CRC cells exhibit resistance to cetuximab, requiring higher drug concentrations for therapeutic effect due to aberrant RAS activation.
  • The variant was classified as 'likely pathogenic' according to ACMG guidelines.

Conclusions:

  • The germline RASAL2 c.2423 A>G variant is likely pathogenic and contributes to CRC progression.
  • This variant confers resistance to anti-EGFR therapy in CRC patients through enhanced RAS/ERK signaling.
  • RASAL2 c.2423 A>G may serve as a valuable biomarker for predicting CRC risk and guiding anti-EGFR treatment strategies.
Keywords:
RASAL2Anti-EGFRColorectal cancerGermline variantPathogenicRAS signalingResistance

More Related Videos

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

3.1K
Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells06:44

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

Published on: March 1, 2024

1.2K

Related Concept Videos

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...
6.4K
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
4.2K
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...
3.9K