Targeting the 'Undruggable' Driver Protein, KRAS, in Epithelial Cancers: Current Perspective

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Epithelial cancers often harbor intracellular driver genes like KRAS.
• Small molecule inhibitors (SMIs) can target intracellular proteins but face challenges like off-target effects and resistance.
• Biologics offer specificity but are limited by cellular entry, though advancements are overcoming this.

Purpose of the Study:

• To review recent developments in synthetic drugs and biologics targeting intracellular genes, particularly KRAS, in epithelial cancers.
• To provide a current perspective and identify potential future directions for cancer therapy.
• To compare the advantages and disadvantages of small molecule inhibitors versus biologics for intracellular targets.

Main Methods:

• Review of recent scientific literature on targeted therapies for epithelial cancers.
• Focus on synthetic drugs (small molecule inhibitors) and biologics.
• Analysis of advancements in targeting KRAS mutations and related therapeutic strategies.

Main Results:

• Engineering of non-covalent KRAS G12D-specific inhibitors.
• Development of probody bispecific antibodies for enhanced targeting.
• Advancements in drug-peptide conjugates for immune response stimulation.
• Successes in adoptive cell therapy for breast and pancreatic cancers.

Conclusions:

• New therapeutic strategies, including novel inhibitors and biologics, show promise for targeting KRAS-driven epithelial cancers.
• Overcoming cellular entry barriers for biologics enhances their potential for specific and less resistance-prone therapy.
• Adoptive cell therapy represents a significant advancement in treating challenging cancers like pancreatic and breast cancer.