An effective way for targeting EGFR-mediated carcinogenesis: an in vitro study

Viktoria A. Pakina; Evgeniya Z. Iksanova; Evgeniya V. Shih; Oksana М. Tumutolova; Karen K. Arutiunian; Irina V. Kargina; Kirill D. Blinov; Fedor P. Pilgaev; Anna A. Epishkina; Dmitrii S. Blinov; Evgeny V. Grebenkin; Ekaterina V. Blinova

doi:10.18413/rrpharmacology.10.453

Authors

Viktoria A. Pakina Sechenov University https://orcid.org/0000-0002-0509-5737
Evgeniya Z. Iksanova Sechenov University https://orcid.org/0000-0002-9098-1214
Evgeniya V. Shih Sechenov University https://orcid.org/0000-0001-6589-7654
Oksana М. Tumutolova N.P. Ogarev National Research Mordovia State University https://orcid.org/0000-0002-8809-6507
Karen K. Arutiunian N.P. Ogarev National Research Mordovia State University https://orcid.org/0000-0002-4797-596X
Irina V. Kargina N.P. Ogarev National Research Mordovia State University https://orcid.org/0009-0007-2643-8368
Kirill D. Blinov Sechenov University https://orcid.org/0009-0002-7195-2191
Fedor P. Pilgaev N.P. Ogarev National Research Mordovia State University https://orcid.org/0000-0002-2036-7657
Anna A. Epishkina LLC «UNIM», National Research Nuclear University MEPHI https://orcid.org/0000-0002-7824-7949
Dmitrii S. Blinov Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology https://orcid.org/0000-0002-8385-4356
Evgeny V. Grebenkin LLC «UNIM», National Research Nuclear University MEPHI https://orcid.org/0000-0002-4990-6722
Ekaterina V. Blinova Sechenov University, National Research Nuclear University MEPHI https://orcid.org/0000-0003-0050-0251

DOI:

https://doi.org/10.18413/rrpharmacology.10.453

Abstract

Introduction: EGFR-activating overexpression or somatic mutations are common in different human cancers. In this regard, the search for promising ways to control the carcinogenic transformation of tumor cells and the progression of malignant tumors expressing EGFR seems to be one of the most promising and developing areas of modern molecular pathology and pharmacology.

Material and Methods: An antitumor activity of a novel compound, a pyridine carboxylic acid derivative LHT-17-19, was studied. The molecule was developed and synthesized at the Department of Chemistry, Drug Design and Technology of All-Russian Research Center for Biological Active Compounds Safety (Russia). The study was carried out in cell cultures of stomach cancer (Hs746T, AGS and MKN1) and patient-derived organoid (PDO) model of breast cancer (BC) expressing wild-type EGFR.

Results: It was shown that LHT-17-19 induced concentration-dependent cytotoxicity of EGFR-expressing gastric cancer cells of all the aforementioned cultures. Pathomorphological, immunohistochemical and molecular validation of BC organoids derived from ductal breast carcinoma cells of a 68-year-old patient was done. PDOs were established as ER-negative, PR-negative, Her2/neu-negative, EGFR-positive with 35% of the Ki-67 expression index. In addition, the tumor cells translocation was resulted in a loss of ER expression and PDOs molecular pattern conversion towards a more aggressive triple negative type. PDOs incubation with 0.5-60.0 µM LHT-17-19 was accompanied not only by inhibition of their growth and proliferation, but also by significant cytoreduction.

Conclusion: Thus, in two-dimensional and three-dimensional tumor cell cultures, the possibility of controlling the oncogenic expression of EGFR with the acridone compound 9-ammonium-3,3-dimethyl-3,4-dihydroacridine-1(2H)-OH L-2-hydroxybutanedivacate (LHT-17-19) was shown.

Graphical Abstract

Explanation: Cytoreductive effect of 9-ammonium-3,3-dimethyl-3,4-dihydroacridine-1(2H)-OH L-2-hydroxybutane against triple negative EGFR-expressing breast cancer cells.

Keywords:

cytotoxicity, EGFR-mediated carcinogenesis, LHT-17-19, patient-derived organoid, pyridine compound, tumor cell cultures

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Author Contribution

Viktoria A. Pakina, Sechenov University

Cand. Sc. (Med), Docent, PhD, Department of Life Safety and Disaster Medicine, Sechenov University, Moscow, Russia; e-mail: shapo-viktoriya@mail.ru, ORCID ID https://orcid.org/0000-0002-0509-5737. Individual contributions: carrying out experiments, data validation, and writing the manuscript.

Evgeniya Z. Iksanova, Sechenov University

M.D., postgraduate student, Department of oncology, Sechenov University, Moscow, Russia; e-mail: ixanovaez@yandex.ru, ORCID ID https://orcid.org/0000-0002-9098-1214. Individual contributions: methodology, data processing, and writing the manuscript.

Evgeniya V. Shih, Sechenov University

D. Med. Sc, Professor, Head of Department of Clinical Pharmacology and Propaedeutics of Internal Diseases, Sechenov University, Moscow, Russia; e-mail: chih@mail.ru, ORCID IDhttps://orcid.org/0000-0001-6589-7654. Individual contributions: conceptualization of the study and data validation.

Oksana М. Tumutolova, N.P. Ogarev National Research Mordovia State University

Cand. Sc. (Med), Docent, PhD, Department of Obstetrics and Gynecology, N.P. Ogarev National Research Mordovia State University, Saransk, Russia; e-mail: tumutolov@mail.ru, ORCID IDhttps://orcid.org/0000-0002-8809-6507. Individual contributions: visualisation and writing the manuscript.

Karen K. Arutiunian , N.P. Ogarev National Research Mordovia State University

M.D., postgraduate student, Department of oncology, N.P. Ogarev National Research Mordovia State University, Saransk, Russia; e-mail: Dr.karen@mail.ru, ORCID ID https://orcid.org/0000-0002-4797-596X. Individual contributions: carrying out experiments and writing the manuscript.

Irina V. Kargina, N.P. Ogarev National Research Mordovia State University

M.D., postgraduate student, Department of oncology, N.P. Ogarev National Research Mordovia State University, Saransk, Russia; e-mail: ir.cargina2014@yandex.ru, ORCID IDhttps://orcid.org/0009-0007-2643-8368. Individual contributions: visualisation and experimental study.

Kirill D. Blinov, Sechenov University

Graduate student, Sechenov University, Moscow, Russia; e-mail: pyrk2@yandex.ru, ORCID IDhttps://orcid.org/0009-0002-7195-2191. Individual contributions: carrying out experiments and writing the manuscript.

Fedor P. Pilgaev, N.P. Ogarev National Research Mordovia State University

V.D., Cand. Sc. (Vet), Docent, Department of Morphology, Physiology and Veterinary Pathology, N.P. Ogarev National Research Mordovia State University, Saransk, Russia; e-mail: pilgaev.fiodor@yandex.ru, ORCID ID https://orcid.org/0000-0002-2036-7657. Individual contributions: experimental study.

Anna A. Epishkina, LLC «UNIM», National Research Nuclear University MEPHI

Cand. Sc. (Med), Docent, PhD, Department of fundamental medicine of National Research Nuclear University MEPHI Pathologist of LLC «UNIM», LLC ”UNIM”, National Research Nuclear University MEPHI, Moscow, Russia; e-mail: afina-nn@mail.ru, ORCID IDhttps://orcid.org/0000-0002-7824-7949. Individual contributions: morphological part of experiments and writing the manuscript.

Dmitrii S. Blinov, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

D. Med. Sc, Professor, Doctor of medical science, head of molecular and clinical pharmacology department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia; e-mail: dmitriy.blinov@fccho-moscow.ru, ORCID ID https://orcid.org/0000-0002-8385-4356. Individual contributions: conceptualization of the study, data validation, statistical analysis, and manuscript draft review.

Evgeny V. Grebenkin, LLC «UNIM», National Research Nuclear University MEPHI

Cand. Sc. (Med), Senior Lecturer of the Department of fundamental medicine of National Research Nuclear University MEPHI of National Research Nuclear University MEPHI; pathologist of LLC ”UNIM”, Moscow, Russia; e-mail: grebenkin_urolog@mail.ru, ORCID IDhttps://orcid.org/0000-0002-4990-6722. Individual contributions: writing the text of the manuscript.

Ekaterina V. Blinova, Sechenov University, National Research Nuclear University MEPHI

D. Med. Sc, Professor, Head of Department of fundamental medicine, Sechenov University, National Research Nuclear University MEPHI, Moscow, Russia; e-mail: bev-sechenov@mail.ru,ORCID ID https://orcid.org/0000-0003-0050-0251. Individual contributions: conceptualization of the study and data validation.