Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Granulocyte-colony stimulating factor (G-CSF) mobilizes myeloid cells and is linked to anti-VEGF therapy resistance and poor cancer prognosis.
• The RAS/MEK/ERK pathway and Ets transcription factors are key regulators in cellular signaling.

Purpose of the Study:

• To elucidate the regulatory mechanism of G-CSF expression.
• To investigate the therapeutic potential of MEK inhibitors in combination with anti-VEGF therapy for cancer treatment.

Main Methods:

• Investigated G-CSF regulation via the RAS/MEK/ERK pathway and Ets transcription factors.
• Utilized in vitro assays to assess MEK inhibitor effects on G-CSF production.
• Evaluated synergistic effects of MEK inhibitors and anti-VEGF antibodies in preclinical cancer models, including pancreatic adenocarcinoma.
• Analyzed patient tumor biopsies for molecular markers and immune cell infiltration.

Main Results:

• Activation of the RAS/MEK/ERK pathway, mediated by Ets transcription factors, was shown to regulate G-CSF expression.
• MEK inhibition significantly reduced G-CSF production in vitro.
• Combination therapy with MEK inhibitors and anti-VEGF antibodies reduced myeloid cell mobilization, tumor growth, and improved survival in animal models.
• Pancreatic cancer patient biopsies showed elevated phospho-MEK, G-CSF, Ets expression, and neutrophil recruitment compared to normal tissue.

Conclusions:

• The MEK/ERK/Ets pathway is a critical regulator of G-CSF production.
• MEK inhibitors represent a promising therapeutic strategy, particularly in combination with anti-VEGF therapy, for enhancing anti-cancer immunity and improving patient survival.
• Findings provide mechanistic insights into MEK inhibitor action and suggest novel therapeutic approaches for various cancers.