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Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
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RALB GTPase: a critical regulator of DR5 expression and TRAIL sensitivity in KRAS mutant colorectal cancer

Hajrah Khawaja1, Andrew Campbell2, Jamie Z Roberts1

  • 1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, UK.

Cell Death & Disease
|October 30, 2020
PubMed

Insights

Inhibition of RALB, not RALA, triggers Caspase-8-dependent cell death in RAS-mutant colorectal cancer. Targeting RALB enhances TRAIL-induced apoptosis, offering a new strategy for poor-prognosis tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • RAS-mutant metastatic colorectal cancer (mCRC) is resistant to current therapies like MEK1/2 inhibitors.
  • RALA and RALB GTPases are downstream effectors of RAS and implicated in KRAS-driven cancers.
  • The role of RALA and RALB in regulating cancer cell apoptosis is not well understood.

Purpose of the Study:

  • To investigate the role of RALA and RALB GTPases in the apoptosis of RAS-mutant colorectal cancer cells.
  • To elucidate the molecular mechanisms by which RALB influences apoptosis.
  • To explore the therapeutic potential of targeting RALB in RAS-mutant mCRC.

Main Methods:

  • RNA interference (RNAi) to inhibit RALA and RALB expression.
  • Caspase-8 activity assays to measure apoptosis.
  • Proteomic analysis to identify molecular targets.
  • TRAIL (TNF-related apoptosis-inducing ligand) treatment and DISC (death-inducing signaling complex) analysis.
  • DR5 (Death Receptor 5) knockdown and knockout experiments.

Main Results:

  • Inhibition of RALB, but not RALA, induced Caspase-8-dependent cell death in KRAS-mutant CRC cells.
  • RALB depletion upregulated the pro-apoptotic receptor DR5, mainly by reducing its lysosomal degradation.
  • DR5 is essential for RALB depletion-induced apoptosis, highlighting the extrinsic apoptotic pathway.
  • Targeting RALB significantly enhanced TRAIL-induced cell death in KRAS-mutant CRC cells.
  • High RALB mRNA levels correlate with poor prognosis in the CRIS-B CRC subgroup.

Conclusions:

  • RALB plays a critical role in regulating apoptosis in RAS-mutant colorectal cancer.
  • RALB inhibition sensitizes cancer cells to TRAIL-induced apoptosis.
  • Targeting RALB represents a promising therapeutic strategy for poor-prognosis RAS-mutant colorectal cancer, particularly within the CRIS-B subtype.

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