EGFR antagonists(University of Parma)

Colorectal cancer (CRC) poses a substantial global health challenge, ranking as the third most commonly diagnosed and second most fatal cancer worldwide. With an increasing incidence, particularly in older populations, CRC demands innovative therapeutic approaches to address the limitations of existing treatments. One critical target in CRC is the KRAS gene, which is frequently mutated and implicated in various cancer-related processes. This narrative review explores the promising role of Sotorasib plus Panitumumab combination therapy in CRC treatment. Combining Sotorasib with Panitumumab, an EGFR antagonist, offers a synergistic approach to comprehensively block KRAS and EGFR pathways, potentially overcoming resistance mechanisms observed in monotherapies. The review discusses the evolution of CRC treatment from traditional chemotherapy to the advent of targeted therapies like Bevacizumab and Cetuximab. It highlights the limitations of existing therapies, including resistance and toxicities, emphasising the urgency for innovative approaches. The CodeBreak clinical trials, specifically CodeBreak 101 and CodeBreak 300, provide a focal point for evaluating the efficacy of Sotorasib plus Panitumumab in patients with refractory KRAS G12C-mutated mCRC. Preliminary results demonstrate significant improvements in progression-free survival (PFS) and objective response rates, suggesting a paradigm shift in CRC treatment. The preliminary findings from the CodeBreak 300 trial signify a transformative impact of Sotorasib plus Panitumumab in refractory KRAS G12C-mutated mCRC. With a notable increase in PFS and objective response rates and a well-tolerated safety profile, this combination therapy emerges as a potential new standard of care. The results present an optimistic outlook for patients resistant to conventional therapies.

Resistance to anti-tumor agents targeting the epidermal growth factor receptor (EGFR) reduces treatment response and requires the development of novel EGFR antagonists. Mutant epidermal growth factor (EGF) forms with reduced agonistic activity could be promising agents in cancer treatment.

EGF D46G affinity to EGFR domain III was assessed with affinity chromatography. EGF D46G acute toxicity in Af albino mice at 320 and 3200 μg/kg subcutaneous doses was evaluated. EGF D46G activity in human epidermoid carcinoma cells at 10 ng/mL concentration in serum-free medium and in subcutaneous Ehrlich ascites carcinoma mice model at 320 μg/kg dose was studied.

The D46G substitution decreases the thermal stability of EGF complexes with EGFR domain III by decreasing the ability of the C-terminus to be released from the intermolecular β- sheet. However, with remaining binding sites for EGFR domain I, EGF D46G effectively competes with other EGF-like growth factors for binding to EGFR and does not demonstrate toxic effects in mice. EGF D46G inhibits the proliferation of human epidermoid carcinoma cells compared to native EGF. A single subcutaneous administration of EGF D46G along with Ehrlich carcinoma cells injection inhibits the proliferation of these cells and delays tumor formation for up to seven days.

EGF D46G can be defined as a partial EGFR agonist as this mutant form demonstrates reduced agonistic activity compared to native EGF. The study emphasizes the role of the EGF C-terminus in establishing interactions with EGFR domain III, which are necessary for EGFR activation and subsequent proliferation of cells.