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Updated: Oct 9, 2025

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KRAS mutation-independent downregulation of MAPK/PI3K signaling in colorectal cancer

Kuen Kuen Lam1, Choong Leong Tang1, Emile Tan1

  • 1Department of Colorectal Surgery, Singapore General Hospital, Singapore.

Molecular Oncology
|December 17, 2021
PubMed

Insights

Targeting KRAS downstream pathways like RAF/MEK/ERK and PI3K/Akt is ineffective in most colorectal cancers. Instead, KRAS-dependent SOX9 upregulation is a key finding in these tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • KRAS is a critical gene in colorectal cancer development.
  • Targeting downstream signaling pathways (RAF/MEK/ERK, PI3K/Akt) has been a focus due to the 'undruggable' nature of KRAS.
  • Previous therapeutic efforts targeting these downstream pathways have not yielded clinical success.

Purpose of the Study:

  • To investigate the activation status of phospho-ERK1/2 and phospho-Akt1/2/3 in human colorectal tumors compared to normal tissue.
  • To explore alternative signaling mechanisms, such as KRAS-dependent SOX9 upregulation, in colorectal tumorigenesis.

Main Methods:

  • Semi-quantitative near-infrared western blot and confocal fluorescence immunohistochemistry imaging were used to analyze protein levels.
  • Publicly available datasets, including The Cancer Genome Atlas (TCGA), NCBI Gene Expression Omnibus (GEO), and Clinical Proteomic Tumor Analysis Consortium (CPTAC), were utilized for validation.

Main Results:

  • A significant majority of colorectal tumors (75.5% for p-ERK1/2, 96.9% for p-Akt1/2/3) exhibited lower or equivalent levels of these signaling proteins compared to matched normal tissue.
  • KRAS-dependent upregulation of SOX9 was observed in 90.3% of the analyzed tumors.
  • These findings were consistent across independent transcriptomics and proteomics datasets.

Conclusions:

  • The RAF/MEK/ERK and PI3K/Akt signaling pathways are unexpectedly not activated in most human colorectal cancers.
  • SOX9 upregulation, dependent on KRAS, represents a potential alternative therapeutic target in colorectal cancer.
Keywords:
CPTACKRAS signalingMAPK/PI3KSOX9TCGAcolorectal tumorigenesis

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