Differential Kinase Activation in Peripheral Blood Mononuclear Cells from Non-Small-Cell Lung Cancer Patients Treated with Nivolumab

Gaëlle Noé,François Goldwasser,Lisa Golmard,Audrey Bellesoeur,Jennifer Arrondeau,Jérome Alexandre,Michel Vidal,Audrey Thomas-Schoemann,Benoit Blanchet,Pascaline Boudou-Rouquette,Manuela Tiako Meyo,Alicja Puszkiel

doi:10.3390/cancers11060762

Abstract

In the era of precision medicine, research of biomarkers for identification of responders to nivolumab therapy is a major challenge. Peripheral blood mononuclear cells (PBMC) could be an interesting surrogate tissue for identifying pharmacodynamic biomarkers. The aim of this exploratory study was to investigate the global serine/threonine kinase (STK) activity in PBMC from non-small-cell lung cancer (NSCLC) patients using a high throughput kinomic profiling method. PamChip® microarrays were used to explore the STK kinomic profile in PBMC from 28 NSCLC patients before nivolumab initiation (D0) and on day 14 (D14) of the first administration. Two clusters of patients (A and B) were identified at D0, median overall survival (OS) tended to be longer in cluster A than in B (402 vs. 112.5 days, respectively; p = 0.15). Interestingly, the PD-L1 tumor cell score (p = 0.045), the count of CD8+ cells (p = 0.023) and the total body weight (p = 0.038) were statistically different between the clusters. On D14, clusters C and D were identified. Greater activity of most STK, especially those of the PI3K/Akt signaling pathway, was noticed among cluster C. No significant difference between C and D was observed regarding OS. Considering the small number of patients, results from this preliminary study are not conclusive. However, the 4-fold longer median OS in cluster A paves the way to further investigate, in a larger cohort of NSCLC patients, the benefit of basal STK kinomic profile in PBMC to identify responders to nivolumab therapy.

Highlights

Lung cancer is the leading cause of cancer death worldwide, with 1.825 million diagnoses and1.59 million deaths in 2012 [1]
Two phase III trials showed that nivolumab improves overall survival, response rate, and progression-free survival compared to docetaxel in patients with advanced, previously treated squamous-cell and nonsquamous non-small-cell lung cancer (NSCLC) [5,6]
Twenty-eight NSCLC patients treated with nivolumab were included

Summary

Introduction

Lung cancer is the leading cause of cancer death worldwide, with 1.825 million diagnoses and. 1.59 million deaths in 2012 [1]. Non-small-cell lung cancer (NSCLC) accounts for 85% to 90% of all lung. A better understanding of the antitumor immunity highlighted the key role of immune checkpoints such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death 1 (PD-1) in immune escape mechanisms [3]. The anti-PD-1 monoclonal antibody nivolumab binds to the PD-1 receptor and blocks its interaction with its ligands. Two phase III trials showed that nivolumab improves overall survival, response rate, and progression-free survival compared to docetaxel in patients with advanced, previously treated squamous-cell and nonsquamous NSCLC [5,6]. Nivolumab is currently approved for the treatment of patients with advanced-stage NSCLC following progression on or after platinum-based chemotherapy

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