Targeting RAS-driven human cancer cells with antibodies to upregulated and essential cell-surface proteins

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Targeting oncogenic RAS signaling has primarily focused on intracellular mechanisms.
• The cell surface of RAS-transformed cells remains an under-explored area for therapeutic intervention.

Purpose of the Study:

• To identify cell-surface protein targets upregulated by oncogenic RAS signaling.
• To develop a platform for targeting RAS-transformed cancer cells from the cell exterior.

Main Methods:

• Quantitative surface proteomics to identify RAS-induced surface proteins.
• Generation of recombinant antibodies against identified targets.
• Cell-surface CRISPRi screening to identify critical signaling pathways.
• In vivo validation of antibody-mediated payload delivery and RAS signaling reporting.

Main Results:

• A signature of proteins upregulated on KRAS^G12V-transformed cells was identified.
• Five of seven tested RAS-induced surface proteins were broadly distributed on RAS-mutated cancer cell lines.
• CDCP1 was identified as a common target through proteomics and CRISPRi screening.
• Antibodies targeting CDCP1 demonstrated efficacy in delivering cytotoxic and immunotherapeutic payloads and reporting RAS signaling status in vivo.

Conclusions:

• A technological platform for targeting RAS signaling from the cell surface has been established.
• CDCP1 is a promising target for antibody-based therapies against RAS-transformed cancers.
• This approach offers a novel strategy for cancer treatment and diagnostics.