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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
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MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells

Akriti Kharbanda1, Hasan Rajabi1, Caining Jin1

  • 1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.

Oncotarget
|September 24, 2014
PubMed

Insights

Targeting MUC1-C in KRAS-mutant non-small cell lung cancer (NSCLC) inhibits AKT/MEK signaling, reverses epithelial-mesenchymal transition (EMT), and reduces tumor growth. This approach offers a new strategy for treating resistant NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology

Background:

  • Non-small cell lung cancer (NSCLC) with KRAS mutations often resists targeted treatments.
  • MUC1-C is overexpressed in NSCLC, correlating with poor prognosis, but its role in KRAS-mutant NSCLC is unknown.

Purpose of the Study:

  • To investigate the functional role of MUC1-C in KRAS-mutant NSCLC cells.
  • To determine if targeting MUC1-C can overcome resistance to targeted therapies in NSCLC.

Main Methods:

  • Silencing MUC1-C in NSCLC cell lines (A549/KRAS(G12S) and H460/KRAS(Q61H)).
  • Utilizing a MUC1-C mutant (CQC→AQA) to inhibit homodimerization and function.
  • Treating cells with GO-203, a MUC1-C homodimerization inhibitor.
  • Analyzing AKT, MEK, ZEB1, and miR-200c signaling pathways.
  • Assessing epithelial-mesenchymal transition (EMT) and self-renewal capacity.
  • Evaluating tumor growth in mice.

Main Results:

  • MUC1-C silencing downregulated AKT signaling and inhibited NSCLC cell growth.
  • MUC1-C mutant overexpression and GO-203 treatment suppressed AKT and MEK activation, decreasing cell survival.
  • Targeting MUC1-C suppressed ZEB1 via AKT, inducing miR-200c, reversing EMT, and inhibiting self-renewal.
  • Loss of MUC1-C function reduced KRAS independence and tumor growth in mice.

Conclusions:

  • MUC1-C plays a critical role in driving signaling pathways in KRAS-mutant NSCLC.
  • Targeting MUC1-C effectively inhibits mutant KRAS signaling, reverses EMT, and reduces self-renewal.
  • MUC1-C inhibition represents a promising therapeutic strategy for KRAS-mutant NSCLC.

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