In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

Abstract

Both ceritinib (CER) and programmed cell death (PD)‐1/PD ligand‐1 (PD‐L1) have brought significant breakthroughs for anaplastic lymphoma kinase (ALK)‐rearranged non‐small‐cell lung cancer (NSCLC). However, the overall clinical efficacy of either CER or PD‐1/PD‐L1 inhibitor monotherapy has been limited to a large extent. In addition, the antitumor effect of combined CER and PD‐L1 inhibitor in ALK‐rearranged NSCLC is not fully understood. In H2228 cells, we examined the tumor killing effect of CER plus PD‐L1 inhibitor in vitro by quantitative RT‐PCR, flow cytometry, ELISA, western blot analysis, PBMC coculture system, and plasmid and transfection experiments. A Ba/F3 (EML4‐ALK‐WT) xenograft mouse model was also utilized to further evaluate the synergistic anticancer effects of CER and PD‐L1 inhibitor in vivo. The coculture system of PBMCs with H2228 cells promotes the expression of PD‐L1 and phospho‐ERK, and combined treatments facilitate lymphocyte proliferation and activation, inhibit PD‐L1 expression, and enhance lymphocyte cytotoxicity and cell death. In the in vivo NSCLC xenograft model, the volumes of tumors treated with CER and PD‐L1 inhibitor in combination were significantly smaller than those treated with CER or PD‐L1 alone. The relative tumor growth inhibitions were 84.9%, 20.0%, and 91.9% for CER, PD‐L1 inhibitor, and CER plus PD‐L1 groups, respectively. Ceritinib could synergize with PD‐1/PD‐L1 blockade to yield enhanced antitumor responses along with favorable tolerability of adverse effects. Ceritinib and PD‐L1 inhibitor combined produced a synergistic antineoplastic efficacy in vitro and in vivo, which provides a key insight and proof of principle for evaluating CER plus PD‐L1 blockade as combination therapy in clinical therapeutic practice.

Anaplastic lymphoma kinase inhibitors—a review of anticancer properties, clinical efficacy, and resistance mechanisms

“…Schäkel et al (2022) demonstrated that ceritinib inhibits ectonuclease CD39 in melanoma and triple negative breast cancer cells, which can contribute to the anti-cancer effects. In addition, in an in vitro experiment, Du and others showed that ceritinib decreases expression of PD-L1 in H2228 cells (NSCLC) through the inhibition of ERK (Du et al, 2020). Moreover, ceritinib was found to induce ICD in NPM1-ALK cells (Petrazzuolo et al, 2021) (Figure 2).…”

Serum Eicosanoids Metabolomics Profile in a Mouse Model of Renal Cell Carcinoma: Predicting the Antitumor Efficacy of Anlotinib

“…Changes in body weight were monitored twice weekly. The percentage of ΔT/C (% of control for Δgrowth) was calculated using the following formula: (ΔT/ΔC) ×100%, where ΔT and ΔC are the changes in tumor volume (Δgrowth) for the treated and control groups, respectively ( 21 ). On the last day of the experiment, all mice were euthanized under carbon dioxide anesthesia, and the tumor tissue was stripped after blood collection.…”

Anaplastic lymphoma kinase-special immunity and immunotherapy

“…A preclinical study showed that in vitro application of ceritinib combined with a PD-L1 inhibitor in the treatment of ALK-rearranged NSCLC promotes lymphocyte proliferation and activation, inhibits PD-L1 expression, and enhances lymphocyte cytotoxicity and cell death. In the in vivo xenograft model, tumor volumes treated with a combination of ceritinib and a PD-L1 inhibitor (91.9%) are significantly smaller than those treated with ceritinib (84.9%) or PD-L1 (20.0%) alone ( 70 ). Some clinical trials have explored the use of ICIs in combination with ALK inhibitors ( 71 , 72 ).…”