Molecular BiologyMolecular BiologyМолекулярная биология0026-89843034-5553The Russian Academy of Sciences69967510.7868/S3034555325060034ОБЗОРЫReview ArticleNovel Approaches to anti-EGFR TherapyСОВРЕМЕННЫЕ ПОДХОДЫ К АНТИ-EGFR-ТЕРАПИИDudkinaE. VДудкинаЕ. Вemail@example.comNadyrovaA. IНадыроваА. Иalsu.nadyrova@yandex.ruLuginskayaS. AЛугинскаяС. Аemail@example.comKosnyrevA. SКосныревА. Сemail@example.comUlyanovaV. VУльяноваВ. Вemail@example.comIlinskayaO. NИльинскаяО. Нemail@example.comInstitute of Fundamental Medicine and Biology, Kazan Federal UniversityИнститут фундаментальной медицины и биологии, Казанский федеральный университет25122025596VOL 59, NO6 (2025)ТОМ 59, №6 (2025)90992727122025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://vietnamjournal.ru/0026-8984/article/view/699675

Epidermal growth factor receptor (EGFR) is one of the most studied proteins in the world. A genuine interest in EGFR is related to its key role in the main conserved signalling pathways responsible for cell growth, survival, and proliferation. Dysregulation of these signalling pathways leads to malignant transformation, promotion of tumour progression, cell migration and invasion. In this regard, EGFR is considered as one of the main targets for anticancer drugs development. Despite several generations of novel anti-EGFR drugs have been successfully developed, acquisition of drug resistance, as well as the mutation status of downstream effector protein KRAS, significantly reduce tumour response to the therapy. This review focuses on the current approaches of anti-EGFR therapy. Here, we will describe drugs aimed at blocking EGFR-mediated signalling, such as monoclonal antibodies, tyrosine kinase inhibitors. Mechanisms of acquired resistance to anti-EGFR therapy will be reviewed, and combination treatment strategies will be proposed. Finally, we will discuss promising antitumor agents including immunotoxins and ribonucleases (RNases) of various origins.

Рецептор эпидермального фактора роста (EGFR) – один из самых изучаемых белков, интерес к которому обусловлен его важной ролью в жизнедеятельности клетки. EGFR регулирует основные высококонсервативные сигнальные пути, контролирующие рост, выживаемость и пролиферацию клеток. Диерегуляция этих сигнальных путей приводит к злокачественной трансформации клеток, прогрессии и метастазированию опухолей. Все это позволяет рассматривать EGFR как одну из основных мишеней для разработки таргетных противопухолевых средств. В настоящее время создано несколько поколений современных анти-EGFR-препаратов, однако, несмотря на все успехи, приобретение клетками лекарственной устойчивости, а также мутационный статус нижележащего в сигнальном пути белка KRAS в конечном итоге снижают ответ опухоли на терапию. В обзоре, посвященном современным тенденциям в таргетной анти-EGFR-терапии, подробно охарактеризованы известные препараты, направленные на блокирование EGFR-опосредованного сигналинга, включая моноклональные антитела, ингибиторы тирозинкиназ и иммунотоксины. Обсуждены механизмы возникновения лекарственной устойчивости в ответ на использование данных лекарственных средств, предложены варианты комбинирования препаратов для повышения эффективности их действия. Кроме того, рассмотрены перспективные противопухолевые агенты, в том числе на основе рибонуклеаз (PHKаз) различного происхождения.

epidermal growth factor receptorEGFRmonoclonal antibodiestyrosine kinase inhibitorsdrug resistanceribonucleasesbinaseрецептор эпидермального фактора ростаEGFRмоноклональные антителаингибиторы тирозинкиназлекарственная устойчивостьрибонуклеазыбиназаРабота выполнена за счет предоставленного в 2024 году Академией наук Республики Татарстан гранта на осуществление фундаментальных и прикладных научных работ в научных и образовательных организациях, предприятиях и организациях реального сектора экономики Республики Татарстан.Martin-Fernandez M.L., Clarke D.T., Roberts S.K., Zanetti-Domingues L.C., Gervasio F.L. (2019) Structure and dynamics of the EGF receptor as revealed by experiments and simulations and its relevance to non-small cell lung cancer. Cells. 8, 316.Lemmon M.A., Schlessinger J. (2010) Cell signaling by receptor tyrosine kinases. Cell. 141, 1117–1134.Shaban N., Kamashev D., Emelianova A., Buzdin A. (2023) Targeted inhibitors of EGFR: structure, biology, biomarkers, and clinical applications. Cells. 13, 47.Rayego-Mateos S., Rodrigues-Diez R., Morgado-Pascual J.L., Valentijn F., Valdivielso J.M., Goldschmeding R., Ruiz-Ortega M. (2018) Role of epidermal growth factor receptor (EGFR) and its ligands in kidney inflammation and damage. Mediators Inflamm. 2018, 8739473.Singh B., Carpenter G., Coffey R.J. (2016) EGF receptor ligands: recent advances. F1000Res. 5, F1000 Faculty Rev-2270.Raja Sharin R.N.F.S., Khan J., Ibahim M.J., Muhamad M., Bowen J., Wan Mohamad Zain W.N.I. (2022) Role of ErbB1 in the underlying mechanism of Lapatinib-induced diarrhoea: a review. Biomed Res. Int. 2022, 4165808.Roepstorff K., Grandal M.V., Henriksen L., Knudsen S.L.J., Lerdrup M., Grøvdal L., Willumsen B.M., van Deurs B. (2009) Differential effects of EGFR ligands on endocytic sorting of the receptor. Traffic. 10, 1115–1127.Wang Y.N., Hung M.C. (2012) Nuclear functions and subcellular trafficking mechanisms of the epidermal growth factor receptor family. Cell Biosci. 2, 13.Singh A.B., Harris R.C. (2005) Autocrine, paracrine and juxtacrine signaling by EGFR ligands. Cell. Signal. 17, 1183–1193.Freed D.M., Bessman N.J., Kiyatkin A., Salazar-Cavazos E., Byrne P.O., Moore J.O., Valley C.C., Ferguson K.M., Leahy D.J., Lidke D.S., Lemmon M.A. (2017) EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics. Cell. 171, 683–695.e18.Zhu M., Wang D.D., Yan H. (2021) Genotype-determined EGFR-RTK heterodimerization and its effects on drug resistance in lung сancer treatment revealed by molecular dynamics simulations. BMC Mol. Cell. Biol. 22, 34.Guo Y.J., Pan W.W., Liu S.B., Shen Z.F., Xu Y., Hu L.L. (2020) ERK/MAPK signalling pathway and tumorigenesis. Exp. Therap. Med. 19, 1997– 2007.Glaviano A., Foo A.S.C., Lam H.Y., Yap K.C.H., Jacot W., Jones R.H., Eng H., Nair M.G., Makvandi P., Geoerger B., Kulke M.H., Baird R.D., Prabhu J.S., Carbone D., Pecoraro C., Teh D.B.L., Sethi G., Cavalieri V., Lin K.H., Javidi-Sharifi N.R., Toska E., Davids M.S., Brown J.R., Diana P., Stebbing J., Fruman D.A., Kumar A.P. (2023) PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol. Cancer. 22, 138.Hu X., Li J., Fu M., Zhao X., Wang W. (2021) The JAK/STAT signaling pathway: from bench to clinic. Sig. Transduct. Target Ther. 6, 402.Cheng W.L., Feng P.H., Lee K.Y., Chen K.Y., Sun W.L., Van Hiep N., Luo C.S., Wu S.M. (2021) The role of EREG/EGFR pathway in tumor progression. Int. J. Mol. Sci. 22, 12828.Pines G., Köstler W.J., Yarden Y. (2010) Oncogenic mutant forms of EGFR: lessons in signal transduction and targets for cancer therapy. FEBS Lett. 584, 2699–2706.Endres N.F., Barros T., Cantor A.J., Kuriyan J. (2014) Emerging concepts in the regulation of the EGF receptor and other receptor tyrosine kinases. Trends Biochem. Sci. 39, 437–446.Franovic A., Gunaratnam L., Smith K., Robert I., Patten D., Lee S. (2007) Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc. Natl. Acad. Sci. USA. 104, 13092– 13097.Ali R., Wendt M. (2017) The paradoxical functions of EGFR during breast cancer progression. Sig. Transduct. Target Ther. 2, 16042.Uribe M.L., Marrocco I., Yarden Y. (2021) EGFR in cancer: signaling mechanisms, drugs, and acquired resistance. Cancers. 13, 2748.Lotfaliansaremia S., Sabioa M., Cornwella S., Tolias P. (2020) Role of the mitogen-activated protein kinase (MAPK) signaling pathway in cancer. Med. Res. Arch. 8, 4.Hsu J.L., Hung M.C. (2016) The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 35, 575–588.Avilés-Salas A., Muñiz-Hernández S., Maldonado-Martínez H.A., Chanona-Vilchis J.G., Ramírez-Tirado L.A., HernáNdez-Pedro N., Dorantes-Heredia R., RuíZ-Morales J.M., Motola-Kuba D., Arrieta O. (2016) Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer. Oncol. Lett. 13, 912–920.Demir D., Parvizi M., Pehlivanoglu B., Ergin E., Ayhan S., Doganavsargil B. (2024) The association of the epidermal growth factor receptor (EGFR) immunoexpression with prognostic parameters in adenocarcinoma patients receiving neoadjuvant treatment. Cureus. 16, e56763.Nicholson R.I., Gee J.M., Harper M.E. (2001) EGFR and cancer prognosis. Eur. J. Cancer. 37, 9–15.Saraon P., Pathmanathan S., Snider J., Lyakisheva A., Wong V., Stagljar I. (2021) Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches. Oncogene. 40, 4079–4093.Muraro E., Fanetti G., Lupato V., Giacomarra V., Steffan A., Gobitti C., Vaccher E., Franchin G. (2021) Cetuximab in locally advanced head and neck squamous cell carcinoma: biological mechanisms involved in efficacy, toxicity and resistance. Crit. Rev. Oncol. Hematol. 164, 103424.Saoudi González N., Ros J., Baraibar I., Salvà F., Rodríguez-Castells M., Alcaraz A., García A., Tabernero J., Élez E. (2024) Cetuximab as a key partner in personalized targeted therapy for metastatic colorectal cancer. Cancers. 16, 412.Zhu C., Guan X., Zhang X., Luan X., Song Z., Cheng X., Zhang W., Qin J.-J. (2022) Targeting KRAS mutant cancers: from druggable therapy to drug resistance. Mol. Cancer. 21, 159.Kopetz S., Murphy D.A., Pu J., Ciardiello F., Desai J., Van Cutsem E., Wasan H.S., Yoshino T., Saffari H., Zhang X., Hamilton P., Xie T., Yaeger R., Tabernero J. (2024) Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial. Nat. Med. 30, 3261–3271.Van Emburgh B.O., Arena S., Siravegna G., Lazzari L., Crisafulli G., Corti G., Mussolin B., Baldi F., Buscarino M., Bartolini A., Valtorta E., Vidal J., Bellosillo B., Germano G., Pietrantonio F., Ponzetti A., Albanell J., Siena S., Sartore-Bianchi A., Di Nicolantonio F., Montagut C., Bardelli A. (2016) Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer. Nat. Commun. 7, 13665.Price T., Ang A., Boedigheimer M., Kim T.W., Li J., Cascinu S., Ruff P., Satya Suresh A., Thomas A., Tjulandin S., Peeters M. (2020) Frequency of S492R mutations in the epidermal growth factor receptor: analysis of plasma DNA from patients with metastatic colorectal cancer treated with panitumumab or cetuximab monotherapy. Cancer Biol. Ther. 21, 891–898.Liao H.-W., Hsu J.-M., Xia W., Wang H.-L., Wang Y.-N., Chang W.-C., Arold S.T., Chou C.-K., Tsou P.-H., Yamaguchi H., Fang Y.-F., Lee H.-J., Lee H.-H., Tai S.-K., Yang M.-H., Morelli M.P., Sen M., Ladbury J.E., Chen C.-H., Grandis J.R., Kopetz S., Hung M.-C. (2015) PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response. J. Clin. Invest. 125, 4529– 4543.Montagut C., Argilés G., Ciardiello F., Poulsen T.T., Dienstmann R., Kragh M., Kopetz S., Lindsted T., Ding C., Vidal J., Clausell-Tormos J., Siravegna G., Sánchez-Martín F.J., Koefoed K., Pedersen M.W., Grandal M.M., Dvorkin M., Wyrwicz L., Rovira A., Cubillo A., Salazar R., Desseigne F., Nadal C., Albanell J., Zagonel V., Siena S., Fumi G., Rospo G., Nadler P., Horak I.D., Bardelli A., Tabernero J. (2018) Efficacy of Sym004 in patients with metastatic colorectal cancer with acquired resistance to anti-EGFR therapy and molecularly selected by circulating tumor DNA analyses: a phase 2 randomized clinical trial. JAMA Oncol. 4, e175245.Fakih M.G., Salvatore L., Esaki T., Modest D.P., Lopez-Bravo D.P., Taieb J., Karamouzis M.V., Ruiz-Garcia E., Kim T.-W., Kuboki Y., Meriggi F., Cunningham D., Yeh K.-H., Chan E., Chao J., Saportas Y., Tran Q., Cremolini C., Pietrantonio F. (2023) Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N. Engl. J. Med. 389, 2125–2139.Wang P., Zhang L., Yu L., Huang C., Wang W. (2024) Successful treatment of GEMOX regimen combined with nimotuzumab in the pancreatic cancer with wild KRAS and mutant BRCA: a report of two cases. AME Case Rep. 8, 99.Murata Y., Tanzawa S., Misumi T., Yoshioka H., Miyauchi E., Ninomiya K., Takeshita M., Ito K., Okamoto T., Sugawara S., Kawashima Y., Hashimoto K., Mori M., Miyanaga A., Hayashi A., Tanaka H., Honda R., Nojiri M., Sato Y., Hata A., Masuda K., Kozuki T., Kawamura T., Suzuki T., Yamaguchi T., Asada K., Tetsumoto S., Tanaka H., Watanabe S., Umeda Y., Yamaguchi K., Kuyama S., Tsuruno K., Misumi Y., Kuraishi H., Yoshihara K., Nakao A., Kubo A., Yokoyama T., Watanabe K., Seki N. (2023) Multicenter, retrospective study to evaluate necitumumab plus cisplatin and gemcitabine after immune checkpoint inhibitors in advanced squamous cell lung cancer in Japan: The NINJA study. JTO Clin. Res. Rep. 4, 100593.Bagchi A., Haidar J.N., Eastman S.W., Vieth M., Topper M., Iacolina M.D., Walker J.M., Forest A., Shen Y., Novosiadly R.D., Ferguson K.M. (2018) Molecular basis for necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance. Mol. Cancer Ther. 17, 521–531.Dhillon S. (2021) Lazertinib: first approval. Drugs. 81, 1107–1113.Cho B.C., Wang Y., Felip E., Cui J., Spira A.I., Neal J.W., Baik C., Marmarelis M.E., Ichihara E., Lee J.-S., Lee S.-H., Yang J.C.-H., Michels S.Y.F., Anastasiou Z., Curtin J.C., Lyu X., Leconte I., Trani L., Baig M., Tomasini P. (2024) Amivantamab plus lazertinib in atypical EGFR -mutated advanced non-small cell lung cancer (NSCLC): results from CHRYSALIS-2. J. Clin. Oncol. 42, 8516.Reis E.S., Mastellos D.C., Ricklin D., Mantovani A., Lambris J.D. (2018) Complement in cancer: untangling an intricate relationship. Nat. Rev. Immunol. 18, 5–18.Ahmed M., Pan D.W., Davis M.E. (2015) Lack of in vivo antibody dependent cellular cytotoxicity with antibody containing gold nanoparticles. Bioconjugate Chem. 26, 812–816.Grinko E.K., Donetskova A.D. (2024). The main approaches for monoclonal antibodies in cancer immunotherapy. Immunologiya. 45, 355–366.Stroh C., Reusch C., Schmidt J., Splittgerber J., Blaukat A. (2010) Pharmacological and immunological characterization of the therapeutic anti-EGFR antibodies cetuximab, panitumumab and matuzumab: the combination of cetuximab and matuzumab results in enhanced effector functions. Proc. 101st Annu. Meet. Am. Assoc. Cancer Res., Apr. 17–21, Washington, DC, Philadelphia (PA): AACR; Cancer Res. 70 (8 Suppl.): Abstract nr LB-316.Martins C.D., Kramer-Marek G., Oyen W.J. (2018) Radioimmunotherapy for delivery of cytotoxic radioisotopes: current status and challenges. Expert Opin. Drug Delivery. 15, 185–196.Bravo M.G., Egorova B.V., Vasiliev A.N., Lapshina E.V., Ermolaev S.V., Durymanov M.O. (2023) DTPA (DOTA)-nimotuzumab radiolabeling with generator-produced thorium for radioimmunotherapy of EGFR-overexpressing carcinomas. Curr. Radiopharmaceut. 16, 233–242.Fu Z., Li S., Han S., Shi C., Zhang Y. (2022) Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct. Target. Ther. 7, 93.Menon S., Parakh S., Scott A.M., Gan H.K. (2022) Antibody-drug conjugates: beyond current approvals and potential future strategies. Explor. Target. Antitumor Ther. 3, 252–277.Xu R.-H., Qiu M.-Z., Zhang Y., Wei X.-L., Hu C. (2020) First-in-human dose-escalation study of anti-EGFR ADC MRG003 in patients with relapsed/ refractory solid tumors. J. Clin. Oncol. 38, 3550.Cohen M.H., Williams G.A., Sridhara R., Chen G., McGuinn Jr W.D., Morse D., Abraham S., Rahman A., Liang C., Lostritto R., Baird A., Pazdur R. (2004) United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. Clin. Cancer Res. 10, 1212–1218.Cohen M.H., Johnson J.R., Chen Y.-F., Sridhara R., Pazdur R. (2005) FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist. 10, 461–466.Ryan Q., Ibrahim A., Cohen M.H., Johnson J., Ko C.-W., Sridhara R., Justice R., Pazdur R. (2008) FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist. 13, 1114–1119.Tan F., Shi Y., Wang Y., Ding L., Yuan X., Sun Y. (2015) Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancer. Future Oncol. 11, 385–397.Abourehab M.A.S., Alqahtani A.M., Youssif B.G.M., Gouda A.M. (2021) Globally approved EGFR inhibitors: Insights into their syntheses, target kinases, biological activities, receptor interactions, and metabolism. Molecules. 26, 6677.Ogino A., Kitao H., Hirano S., Uchida A., Ishiai M., Kozuki T., Takigawa N., Takata M., Kiura K., Tanimoto M. (2007) Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non-small cell lung cancer cell line. Cancer Res. 67, 7807–7814.Sequist L.V., Yang J.C.-H., Yamamoto N., O’Byrne K., Hirsh V., Mok T., Geater S.L., Orlov S., Tsai C.-M., Boyer M., Su W.-C., Bennouna J., Kato T., Gorbunova V., Lee K.H., Shah R., Massey D., Zazulina V., Shahidi M., Schuler M. (2023) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 41, 2869–2876.Wu Y.-L., Cheng Y., Zhou X., Lee K.H., Nakagawa K., Niho S., Tsuji F., Linke R., Rosell R., Corral J., Migliorino M.R., Pluzanski A., Sbar E.I., Wang T., White J.L., Nadanaciva S., Sandin R., Mok T.S. (2017) Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 18, 1454–1466.Burstein H.J., Sun Y., Dirix L.Y., Jiang Z., Paridaens R., Tan A.R., Awada A., Ranade A., Jiao S., Schwartz G., Abbas R., Powell C., Turnbull K., Vermette J., Zacharchuk C., Badwe R. (2010) Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J. Clin. Oncol. 28, 1301–1307.Solca F., Dahl G., Zoephel A., Bader G., Sanderson M., Klein C., Kraemer O., Himmelsbach F., Haaksma E., Adolf G.R. (2012) Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J. Pharmacol. Exp. Ther. 343, 342–350.Cohen P., Cross D., Jänne P.A. (2021) Kinase drug discovery 20 years after imatinib: progress and future directions. Nat. Rev. Drug Discov. 20, 551–569.Park K., Tan E.-H., O’Byrne K., Zhang L., Boyer M., Mok T., Hirsh V., Yang J.C., Lee K.-H., Lu S., Shi Y., Kim S.-W., Laskin J., Kim D.-W., Arvis C.D., Kölbeck K., Laurie S.A., Tsai C.-M., Shahidi M., Kim M., Massey D., Zazulina V., Paz-Ares L. (2016) Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 17, 577–589.Jackson P.A., Widen J.C., Harki D.A., Brummond K.M. (2017) Covalent modifiers: a chemical perspective on the reactivity of α,β-unsaturated carbonyls with thiols via hetero-Michael addition reactions. J. Med. Chem. 60, 839–885.Remon J., Planchard D. (2015) AZD9291 in EGFR-mutant advanced non-small-cell lung cancer patients. Future Oncol. 11, 3069–3081.Ballard P., Yates J.W.T., Yang Z., Kim D.-W., Yang J.C.-H., Cantarini M., Pickup K., Jordan A., Hickey M., Grist M., Box M., Johnström P., Varnäs K., Malmquist J., Thress K.S., Jänne P.A., Cross D. (2016) Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin. Cancer Res. 22, 5130–5140.Yang K., Ren X., Tao L., Wang P., Jiang H., Shen L., Zhao Y., Cui Y., Li M., Lin S. (2019) Prognostic implications of epidermal growth factor receptor variant III expression and nuclear translocation in Chinese human gliomas. Chin. J. Cancer Res. 31, 188–202.Mok T.S., Wu Y.-L., Ahn M.-J., Garassino M.C., Kim H.R., Ramalingam S.S., Shepherd F.A., He Y., Akamatsu H., Theelen W.S.M.E., Lee C.K., Sebastian M., Templeton A., Mann H., Marotti M., Ghiorghiu S., Papadimitrakopoulou V.A., AURA3 Investigators. (2017) Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640.Ercan D., Xu C., Yanagita M., Monast C.S., Pratilas C.A., Montero J., Butaney M., Shimamura T., Sholl L., Ivanova E.V., Tadi M., Rogers A., Repellin C., Capelletti M., Maertens O., Goetz E.M., Letai A., Garraway L.A., Lazzara M.J., Rosen N., Gray N.S., Wong K.K., Jänne P.A. (2012) Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov. 2, 934–947.Wu L., Ke L., Zhang Z., Yu J., Meng X. (2020) Development of EGFR TKIs and options to manage resistance of third-generation EGFR TKI osimertinib: Conventional ways and immune checkpoint inhibitors. Front. Oncol. 10, 602762.Shi K., Wang G., Pei J., Zhang J., Wang J., Ouyang L., Wang Y., Li W. (2022) Emerging strategies to overcome resistance to third-generation EGFR inhibitors. J. Hematol. Oncol. 15, 94.Niederst M.J., Hu H., Mulvey H.E., Lockerman E.L., Garcia A.R., Piotrowska Z., Sequist L.V., Engelman J.A. (2015) The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin. Cancer Res. 21, 3924–3933.Zhu V.W., Klempner S.J., Ou S.-H.I. (2019) Receptor tyrosine kinase fusions as an actionable resistance mechanism to EGFR TKIs in EGFR-mutant non-small-cell lung cancer. Trends Cancer. 5, 677–692.Ricordel C., Friboulet L., Facchinetti F., Soria J.-C. (2018) Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer. Ann. Oncol. 29, i28–i37.Sequist L.V., Waltman B.A., Dias-Santagata D., Digumarthy S., Turke A.B., Fidias P., Bergethon K., Shaw A.T., Gettinger S., Cosper A.K., Akhavanfard S., Heist R.S., Temel J., Christensen J.G., Wain J.C., Lynch T.J., Vernovsky K., Mark E.J., Lanuti M., Iafrate A.J., Mino-Kenudson M., Engelman J.A. (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26.Weng C.-H., Chen L.-Y., Lin Y.-C., Shih J.-Y., Lin Y.-C., Tseng R.-Y., Chiu A.-C., Yeh Y.-H., Liu C., Lin Y.-T., Fang J.-M., Chen C.-C. (2019) Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI. Oncogene. 38, 455–468.Du X., Yang B., An Q., Assaraf Y.G., Cao X., Xia J. (2021) Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors. Innovation (Cambridge (Mass.)). 2, 100103.Wang Z., Yang J.-J., Huang J., Ye J.-Y., Zhang X.-C., Tu H.-Y., Han-Zhang H., Wu Y.-L. (2017) Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of firstand third-generation EGFR TKIs and shifts allelic configuration at resistance. J. Thorac. Oncol. 12, 1723–1727.Rotow J.K., Costa D.B., Paweletz C.P., Awad M.M., Marcoux P., Rangachari D., Barbie D.A., Sands J., Cheng M.L., Johnson B.E., Oxnard G.R., Jackman D.M., Kwiatkowski D.J., Kehl K.L., Izdebski M.D., Lau C.J., Vasquez K.A., Janne P.A. (2020) Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated non-small cell lung cancer (NSCLC). J. Clin. Oncol. 38, 9507.Camidge D.R., Kim H.R., Ahn M.-J., Yang J.C.H., Han J.-Y., Hochmair M.J., Lee K.H., Delmonte A., Garcia Campelo M.R., Kim D.-W., Griesinger F., Felip E., Califano R., Spira A.I., Gettinger S.N., Tiseo M., Lin H.M., Liu Y., Vranceanu F., Niu H., Zhang P., Popat S. (2021) Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. J. Thorac. Oncol. 16, 2091–2108.Wang X., Zhou L., Yin J.C., Wu X., Shao Y.W., Gao B. (2019) Lung adenocarcinoma harboring EGFR 19del/C797S/T790M triple mutations responds to brigatinib and anti-EGFR antibody combination therapy. J. Thorac. Oncol. 14, e85–e88.Zhao J., Zou M., Lv J., Han Y., Wang G., Wang G. (2018) Effective treatment of pulmonary adenocarcinoma harboring triple EGFR mutations of L858R, T790M, and cis-C797S by osimertinib, bevacizumab, and brigatinib combination therapy: a case report. Onco. Targets. Ther. 11, 5545–5550.He J., Zhou Z., Sun X., Yang Z., Zheng P., Xu S., Zhu W. (2021) The new opportunities in medicinal chemistry of fourth-generation EGFR inhibitors to overcome C797S mutation. Eur. J. Med. Chem. 210, 112995.Das D., Xie L., Hong J. (2024) Next-generation EGFR tyrosine kinase inhibitors to overcome C797S mutation in non-small cell lung cancer (2019–2024) RSC Med. Chem. 15, 3371–3394.Maity P., Chatterjee J., Patil K.T., Arora S., Katiyar M.K., Kumar M., Samarbakhsh A., Joshi G., Bhutani P., Chugh M., Gavande N.S., Kumar R. (2023) Targeting the epidermal growth factor receptor with molecular degraders: state-of-the-art and future opportunities. J. Med. Chem. 66, 3135–3172.Shaw J.P., Akiyoshi D.E., Arrigo D.A., Rhoad A.E., Sullivan B., Thomas J., Genbauffe F.S., Bacha P., Nichols J.C. (1991) Cytotoxic properties of DAB486EGF and DAB389EGF, epidermal growth factor (EGF) receptor-targeted fusion toxins. J. Biol. Chem. 266, 21118–21124.Bauer M., Jorda A., Al-Jalali V., Wölfl-Duchek M., Bergmann F., Nussbaumer-Pröll A., Steindl A., Guggenberger R., Bischof S., Wimmer D., Idzko M., Zeitlinger M. (2024) Phase I dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an inhaled recombinant human ACE2. ERJ Open Res. 10, 567–2023.Niesen J., Stein C., Brehm H., Hehmann-Titt G., Fendel R., Melmer G., Fischer R., Barth S. (2015) Novel EGFR-specific immunotoxins based on panitumumab and cetuximab show in vitro and ex vivo activity against different tumor entities. J. Cancer Res. Clin. Oncol. 141, 2079–2095.Paolillo M., Boselli C., Schinelli S. (2018) Glioblastoma under siege: an overview of current therapeutic strategies. Brain Sci. 8, 15.Kuan C.T., Wikstrand C.J., Archer G., Beers R., Pastan I., Zalutsky M.R., Bigner D.D. (2000) Increased binding affinity enhances targeting of glioma xenografts by EGFRvIII-specific scFv. Int. J. Cancer. 88, 962–969.Forouharmehr A., Nassiri M., Ghovvati Roudsari S., Javadmanesh A. (2020) Production and introduction of a novel immunotoxin based on engineered RNase A for inducing death to HER1-positive cell lines. J. Cell. Physiol. 235, 4679–4687.Leich F., Stöhr N., Rietz A., Ulbrich-Hofmann R., Arnold U. (2007) Endocytotic internalization as a crucial factor for the cytotoxicity of ribonucleases. J. Biol. Chem. 282, 27640–27646.Lomax J.E., Bianchetti C.M., Chang A., Phillips Jr G.N., Fox B.G., Raines R.T. (2014) Functional evolution of ribonuclease inhibitor: insights from birds and reptiles. J. Mol. Biol. 426, 3041–3056.Akbarzadeh-Khiavi M., Safary A., Barar J., Farzi-Khajeh H., Barzegari A., Mousavi R., Somi M.H., Omidi Y. (2020) PEGylated gold nanoparticles-ribonuclease induced oxidative stress and apoptosis in colorectal cancer cells. BioImpacts. 10, 27–36.Jafary B., Akbarzadeh-Khiavi M., Farzi-Khajeh H., Safary A., Adibkia K. (2025) EGFR-targeting RNase A-cetuximab antibody-drug conjugate induces ROS-mediated apoptosis to overcome drug resistance in KRAS mutant cancer cells. Sci. Rep. 15, 1483.Asrorov A.M., Muhitdinov B., Tu B., Mirzaakhmedov S., Wang H., Huang Y. (2022) Advances on delivery of cytotoxic enzymes as anticancer agents. Molecules. 27, 3836.Matousek J., Gotte G., Pouckova P., Soucek J., Slavik T., Vottariello F., Libonati M. (2003) Antitumor activity and other biological actions of oligomers of ribonuclease A. J. Biol. Chem. 278, 23817–23822.Patutina O., Mironova N., Ryabchikova E., Popova N., Nikolin V., Kaledin V., Vlassov V., Zenkova M. (2011) Inhibition of metastasis development by daily administration of ultralow doses of RNase A and DNase I. Biochimie. 93, 689–696.Montioli R., Campagnari R., Fasoli S., Fagagnini A., Caloiu A., Smania M., Menegazzi M., Gotte G. (2021) RNase A domain-swapped dimers produced through different methods: structure-catalytic properties and antitumor activity. Life (Basel). 11, 168.Mohamed I.S.E., Sen’kova A.V., Markov O.V., Markov A.V., Savin I.A., Zenkova M.A., Mironova N.L. (2022) Bovine pancreatic RNase A: an insight into the mechanism of antitumor activity in vitro and in vivo. Pharmaceutics. 14, 1173.Johnson R.J., McCoy J.G., Bingman C.A., Phillips G.N., Raines R.T. (2007) Inhibition of human pancreatic ribonuclease by the human ribonuclease inhibitor protein. J. Mol. Biol. 368, 434–449.Wang Y.-N., Lee H.-H., Chou C.-K., Yang W.-H., Wei Y., Chen C.-T., Yao J., Hsu J.L., Zhu C., Ying H., Ye Y., Wang W.-J., Lim S.-O., Xia W., Ko H.-W., Liu X., Liu C.-G., Wu X., Wang H., Li D., Prakash L.R., Katz M.H., Kang Y., Kim M., Fleming J.B., Fogelman D., Javle M., Maitra A., Hung M.-C. (2018) Angiogenin/ribonuclease 5 is an EGFR ligand and a serum biomarker for erlotinib sensitivity in pancreatic cancer. Cancer Cell. 33, 752–769.Torrent M., Badia M., Moussaoui M., Sanchez D., Nogués M.V., Boix E. (2010) Comparison of human RNase 3 and RNase 7 bactericidal action at the Gram-negative and Gram-positive bacterial cell wall. FEBS J. 277, 1713–1725.Lu L., Li J., Moussaoui M., Boix E. (2018) Immune modulation by human secreted RNases at the extracellular space. Front. Immunol. 9, 1012.Lu L., Wei R., Prats-Ejarque G., Goetz M., Wang G., Torrent M., Boix E. (2021) Human RNase3 immune modulation by catalytic-dependent and independent modes in a macrophage-cell line infection model. Cell. Mol. Life Sci. 78, 2963–2985.Hardbower D.M., Singh K., Asim M., Verriere T.G., Olivares-Villagómez D., Barry D.P., Allaman M.M., Washington M.K., Peek Jr R.M., Piazuelo M.B., Wilson K.T. (2016) EGFR regulates macrophage activation and function in bacterial infection. J. Clin. Invest. 126, 3296–3312.Kalinowski A., Galen B.T., Ueki I.F., Sun Y., Mulenos A., Osafo-Addo A., Clark B., Joerns J., Liu W., Nadel J.A., Dela Cruz C.S., Koff J.L. (2018) Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium. Mucosal Immunol. 11, 958–967.Minutti C.M., Drube S., Blair N., Schwartz C., McCrae J.C., McKenzie A.N., Kamradt T., Mokry M., Coffer P.J., Sibilia M., Sijts A.J., Fallon P.G., Maizels R.M., Zaiss D.M. (2017) Epidermal growth factor receptor expression licenses type-2 helper T cells to function in a T cell receptor-independent fashion. Immunity. 47, 710–722.e6.Dudkina E.V., Ulyanova V.V., Ilinskaya O.N. (2020) Supramolecular organization as a factor of ribonuclease cytotoxicity. Acta Naturae. 12, 24–33.Ilinskaya O.N., Singh I., Dudkina E., Ulyanova V., Kayumov A., Barreto G. (2016) Direct inhibition of oncogenic KRAS by Bacillus pumilus ribonuclease (binase). Biochim. Biophys. Acta. 1863, 1559–1567.Dudkina E., Ulyanova V., Asmandiyarova V., Vershinina V., Ilinskaya O. (2024) Two main cancer biomarkers as molecular targets of binase antitumor activity. Biomed. Res. Int. 2024, 8159893.Rubio K., Romero-Olmedo A.J., Sarvari P., Swaminathan G., Ranvir V.P., Rogel-Ayala D.G., Cordero J., Günther S., Mehta A., Bassaly B., Braubach P., Wygrecka M., Gattenlöhner S., Tresch A., Braun T., Dobreva G., Rivera M.N., Singh I., Graumann J., Barreto G. (2023) Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer. Theranostics. 13, 2384–2407.