Department of General Chemistry, Belarusian State Medical University, Dzerzhinskogo 83, Minsk, 220083, Belarus.
Institute of Physiology, National Academy of Sciences of Belarus, Academicheskaya 28, Minsk, 220072, Belarus.
Protein Pept Lett. 2024;31(7):504-518. doi: 10.2174/0109298665297321240708044223.
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.
针对表皮生长因子受体（EGFR）的抗肿瘤药物的耐药性降低了治疗反应，需要开发新的 EGFR 拮抗剂。具有降低激动活性的突变表皮生长因子（EGF）形式可能是癌症治疗的有前途的药物。
使用亲和层析法评估 EGF D46G 与 EGFR 结构域 III 的亲和力。在 320 和 3200μg/kg 皮下剂量下，评估 EGF D46G 在 Af 白化小鼠中的急性毒性。在无血清培养基中浓度为 10ng/mL 的人表皮样癌细胞中和在 320μg/kg 剂量的皮下 Ehrlich 腹水癌细胞小鼠模型中研究 EGF D46G 的活性。
D46G 取代降低了 EGF 与 EGFR 结构域 III 复合物的热稳定性，降低了 C 末端从分子间β-片层释放的能力。然而，由于仍然存在与 EGFR 结构域 I 的结合位点，EGF D46G 可以有效地与其他 EGF 样生长因子竞争与 EGFR 的结合，并且在小鼠中没有表现出毒性作用。与天然 EGF 相比，EGF D46G 抑制人表皮样癌细胞的增殖。与 Ehrlich 癌细胞注射一起单次皮下给予 EGF D46G 可抑制这些细胞的增殖，并延迟肿瘤形成长达七天。
EGF D46G 可被定义为部分 EGFR 激动剂，因为与天然 EGF 相比，这种突变形式显示出降低的激动活性。该研究强调了 EGF C 末端在与 EGFR 结构域 III 建立相互作用中的作用，这对于 EGFR 激活和随后的细胞增殖是必要的。
