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Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies
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Selective inhibition of stemness through EGFR/FOXA2/SOX9 axis reduces pancreatic cancer metastasis

Garima Kaushik1, Parthasarathy Seshacharyulu1, Sanchita Rauth1

  • 1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.

Oncogene
|December 8, 2020
PubMed

Insights

Pancreatic cancer stem cell (PCSC) eradication is key to overcoming drug resistance. Combining afatinib with gemcitabine effectively reduced PCSC growth and metastasis by targeting the EGFR/ERK/FOXA2/SOX9 pathway.

Area of Science:

  • Oncology
  • Cancer Biology
  • Pharmacology

Background:

  • Pancreatic cancer (PC) is challenging due to metastasis and drug resistance, often driven by cancer stemness.
  • Pancreatic cancer stem cells (PCSCs) significantly contribute to PC's aggressive nature and therapeutic limitations.

Purpose of the Study:

  • To evaluate the pre-clinical and clinical significance of eradicating PCSCs using afatinib, a pan-EGFR inhibitor, in combination with gemcitabine.
  • To elucidate the molecular mechanisms underlying the combination therapy's efficacy against PC stemness and metastasis.

Main Methods:

  • Utilized genetically engineered mouse models (KrasG12D/+; Pdx-1 Cre and KrasG12D/+; p53R172H/+; Pdx-1 Cre), murine cell lines, and patient-derived organoids.
  • Assessed tumor burden, metastasis incidence, stemness markers (SOX9), and signaling pathways (EGFR, ERK, FAK, FOXA2) via co-localization and molecular analyses.
  • Validated findings using publicly available datasets and analyzed effects on chemotherapy-treated versus chemo-naïve patients.

Main Results:

  • The combination of afatinib and gemcitabine significantly reduced tumoroid, cell line, and xenograft tumor growth compared to monotherapy.
  • The drug combination decreased metastasis and key stemness markers, including SOX9, which was overexpressed in high-grade PC and chemotherapy-treated patients.
  • Afatinib inhibited PCSCs and tumorsphere formation by reducing EGFR family protein phosphorylation and downregulating SOX9 via the EGFR/ERK/FOXA2 axis.

Conclusions:

  • Pan-EGFR inhibition by afatinib effectively impedes PCSC growth and metastasis through the EGFR/ERK/FOXA2/SOX9 signaling pathway.
  • This combination therapy offers a novel strategy to enhance chemotherapeutic benefits by targeting cancer stemness in pancreatic cancer.
  • The findings suggest potential applicability of this approach in other cancer types exhibiting similar stemness-driven resistance mechanisms.

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