Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer

Abstract

Platinum-based chemotherapy remains the cornerstone of treatment for most people with non-small cell lung cancer (NSCLC), either as adjuvant therapy in combination with a second cytotoxic agent or in combination with immunotherapy. Resistance to therapy, either in the form of primary refractory disease or evolutionary resistance, remains a significant issue in the treatment of NSCLC. Hence, predictive biomarkers and novel combinational strategies are required to improve the effectiveness and durability of treatment response 6for people with NSCLC. The aim of this study was to identify novel biomarkers and/or druggable proteins from deregulated protein networks within non-oncogene driven disease that are involved in the cellular response to cisplatin. Following exposure of NSCLC cells to cisplatin, in vitro quantitative mass spectrometry was applied to identify altered protein response networks. A total of 65 proteins were significantly deregulated following cisplatin exposure. These proteins were assessed to determine if they are druggable targets using novel machine learning approaches and to identify whether these proteins might serve as prognosticators of platinum therapy. Our data demonstrate novel candidates and drug-like molecules warranting further investigation to improve response to platinum agents in NSCLC.

Exploring the Molecular Players behind the Potentiation of Chemotherapy Effects by Durvalumab in Lung Adenocarcinoma Cell Lines

“…On the other hand, the addition of a chemotherapeutic agent to the treatment mixture was generally associated with increased levels of the cell cycle-related proteins (indicating cell cycle arrest) and decreased levels of the histones (indicating nucleosome degradation during apoptosis). In line with the literature [ 20 , 21 , 22 ], treatment with the pemetrexed-containing mixtures triggered increases in DHFR, and treatment with both the cisplatin- and pemetrexed-containing mixtures triggered increases in TYMS across the cell lines. In A549, treatment with the chemotherapeutic drug-containing mixtures also caused an elevation of FDXR.…”

Inhibition of Aurora B kinase (AURKB) enhances the effectiveness of 5-fluorouracil chemotherapy against colorectal cancer cells

“…This cell line was selected as a commonly utilised CRC cell line for in vitro assays. We have previously employed this approach in non-small cell lung cancer (NSCLC) cells to identify proteins deregulated by chemotherapeutic agents that could be exploitable to improve sensitivity to chemotherapy [ 20 ]. Quantitative proteomics identified 3590 proteins, whereby 1512 proteins were downregulated by 5-FU treatment and 2078 proteins were upregulated (Supplemental Table 1 ).…”

Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer

“…The identification of novel biomarkers that are predictive of tumour relapse or TKI resistance is key to improving the health outcomes for NSCLC patients with tumours harbouring EGFR activating mutations. More recently, we have identified novel protein-based NSCLC biomarkers with prognostic potential [ 23 ] including cell division cycle-associated protein-3 (CDCA3) [ 24 , 25 ]. CDCA3, also referred to as trigger of mitosis entry 1 (TOME-1), was first reported as a modulator of cell cycle progression for entry into mitosis from the G2 phase [ 26 ].…”