Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Pancreatic cancer remains a challenging disease with limited treatment options.
• Molecular-targeted therapies and immune-checkpoint inhibitors (ICIs) are emerging as promising treatment modalities.
• The intersection of these therapies offers potential for novel treatment strategies.

Purpose of the Study:

• To investigate the efficacy of combining CDK4/6 and MEK inhibitors with ICIs for pancreatic cancer treatment.
• To elucidate the impact of this combination therapy on the tumor microenvironment and immune response.

Main Methods:

• Utilized patient-derived cell lines and xenograft models to assess response to CDK4/6 and MEK inhibition.
• Employed subcutaneous and orthotopic syngeneic models to evaluate combination effects with immunotherapy.
• Applied single-cell RNA sequencing and multispectral imaging to analyze changes in the tumor immune microenvironment.

Main Results:

• Combination treatment with MEK and CDK4/6 inhibitors effectively delayed tumor progression in various pancreatic ductal adenocarcinoma (PDAC) models.
• Observed stable cell-cycle arrest and induction of interferon response and antigen presentation genes in an RB-dependent manner.
• Demonstrated increased T-cell infiltration, altered myeloid populations, and synergistic effects with ICIs.

Conclusions:

• CDK4/6 and MEK inhibition exhibit canonical and non-canonical effects on the tumor and immune microenvironment.
• Combination therapy shows potential for robust tumor control when combined with ICIs.
• This targeted approach represents a promising strategy for enhancing pancreatic cancer treatment outcomes.