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CKD-516 potentiates the anti-cancer activity of docetaxel against epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer

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Abstract

Lung cancer is the leading cause of cancer death. Although docetaxel has been used as a second- or third-line treatment for non-small cell lung cancer (NSCLC), the objective response rate is less than 10%. Hence, there is a need to improve the clinical efficacy of docetaxel monotherapy; combination therapy should be considered. Here, we show that CKD-516, a vascular disruption agent, can be combined with docetaxel to treat epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant NSCLC. CKD-516 was orally bioavailable; neither CKD-516 nor docetaxel affected the mean plasma concentration–time profile or pharmacokinetic parameters of the other drug. CKD-516 and docetaxel synergistically inhibited the growth of H1975 (with an L858R/T790M double mutation of EGFR) and A549 (with a KRAS mutation) lung cancer cell lines. In addition, docetaxel plus CKD-516 delayed tumor growth in—and extended the lifespan of—tumor-bearing mice. Thus, combination CKD-516 and docetaxel therapy could be used to treat EGFR-TKI-resistant NSCLC.

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Abbreviations

ANOVA:

Analysis of variance

AUC:

Area under the curve

BA:

Bioavailability

BSC:

Best supportive care

CD31:

Cluster of differentiation 31

CDK:

Cyclin-dependent kinase

CYP:

Cytochrome P450

DC:

Dendritic cell

DCE:

Dynamic contrast-enhanced

DDI:

Drug-drug interaction

EGFR:

Epidermal growth factor receptor

FACS:

Fluorescence activated cell sorting

IACUC:

Institutional animal care and use committee

ICI:

Immune checkpoint inhibitor

i.p. :

Intraperitoneal

i.v. :

Intravenous

JNK:

C-Jun N-terminal kinase

KRAS:

Kirsten rat sarcoma viral oncogene homolog

LC–MS/MS:

Liquid chromatography tandem-mass spectrometry

MHC:

Major histocompatibility complex

MRI:

Magnetic resonance imaging

NADPH:

Nicotinamide adenine dinucleotide phosphate

n.c.:

Not calculated

n.d.:

Not determined

NSCLC:

Non-small cell lung cancer

ORR:

Objective response rate

OS:

Overall survival

PK:

Pharmacokinetics

p.o. :

Per os

q.d. :

Quaque die

SD:

Sprague–Dawley

TKI:

Tyrosine kinase inhibitor

VDA:

Vascular disrupting agent

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Acknowledgements

This research was funded by the National Research Foundation of Korea (NRF) grant 2021R1A2C2093196.

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Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea

    Soo Jin Kim, Jaewoo Park, Miso Park & Keon Wook Kang

  2. CKD Research Institution, Chong Kun Dang Pharmaceutical Corporation, 16995, Gyeonggi-do, Republic of Korea

    Soo Jin Kim, Kyunghyeon Lee, U. Ji Kim, Se-mi Kim & Keun Ho Ryu

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  1. Soo Jin Kim
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Correspondence to Keon Wook Kang.

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Soo Jin Kim, Kyunghyeon Lee, U Ji Kim, Se-mi Kim and Keun Ho Ryu works in CKD Research Institution, Chong Kun Dang Pharmacuetical Corporation.

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Kim, S.J., Lee, K., Park, J. et al. CKD-516 potentiates the anti-cancer activity of docetaxel against epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer. Toxicol Res. 39, 61–69 (2023). https://doi.org/10.1007/s43188-022-00146-0

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