Human blood serum can donor-specifically antagonize effects of EGFR-targeted drugs on squamous carcinoma cell growth

Dmitry Kamashev; Maksim Sorokin; Irina Kochergina; Aleksey Drobyshev; Uliana Vladimirova; Marianna Zolotovskaia; Igor Vorotnikov; Nina Shaban; Mikhail Raevskiy; Denis Kuzmin; Anton Buzdin

doi:10.1016/j.heliyon.2021.e06394

Human blood serum can donor-specifically antagonize effects of EGFR-targeted drugs on squamous carcinoma cell growth

Heliyon. 2021 Mar 11;7(3):e06394. doi: 10.1016/j.heliyon.2021.e06394. eCollection 2021 Mar.

Authors

Dmitry Kamashev^{1

2}, Maksim Sorokin^{1

2

3}, Irina Kochergina¹, Aleksey Drobyshev^{1

2

3}, Uliana Vladimirova^{1

2}, Marianna Zolotovskaia³, Igor Vorotnikov⁴, Nina Shaban^{1

3}, Mikhail Raevskiy^{3

5}, Denis Kuzmin³, Anton Buzdin^{1

2

3}

Affiliations

¹ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
² World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, 8-2, Trubetskaya St., Moscow 119992, Russia.
³ Moscow Institute of Physics and Technology (National Research University), Moscow Region 141700, Russia.
⁴ Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia.
⁵ OmicsWay Corp., Walnut, CA, USA.

Abstract

Many patients fail to respond to EGFR-targeted therapeutics, and personalized diagnostics is needed to identify putative responders. We investigated 1630 colorectal and lung squamous carcinomas and 1357 normal lung and colon samples and observed huge variation in EGFR pathway activation in both cancerous and healthy tissues, irrespectively on EGFR gene mutation status. We investigated whether human blood serum can affect squamous carcinoma cell growth and EGFR drug response. We demonstrate that human serum antagonizes the effects of EGFR-targeted drugs erlotinib and cetuximab on A431 squamous carcinoma cells by increasing IC50 by about 2- and 20-fold, respectively. The effects on clonogenicity varied significantly across the individual serum samples in every experiment, with up to 100% differences. EGF concentration could explain many effects of blood serum samples, and EGFR ligands-depleted serum showed lesser effect on drug sensitivity.

Keywords: A431; Cetuximab; Colorectal cancer; Drug resistance; EGF; EGFR; Erlotinib; HER-targeted therapy; Human blood serum; Lung cancer; NRG; Neuregulin; Squamous cell carcinoma; TGF-alpha; Trastuzumab.