Abstract

BackgroundThe identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures.MethodsGene fitness was determined by bioinformatics analysis from available datasets from genetic screenings. HSPD1 expression was evaluated by immunohistochemistry from formalin-fixed paraffin-embedded tissues from NSCLC patients. Real-time proliferation assays with and without cytotoxicity reagents, colony formation assays and cell cycle analyses were used to monitor growth and drug sensitivity of different NSCLC cells in vitro. In vivo growth was monitored with subcutaneous injections in immune-deficient mice. Cell metabolic activity was analyzed through extracellular metabolic flux analysis. Specific knockouts were introduced by CRISPR/Cas9.ResultsWe show heat shock protein family D member 1 (HSPD1 or HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients’ prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on oxidative phosphorylation and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B.ConclusionsThese results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NSCLC.

Highlights

  • The identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide

  • heat shock protein family D member 1 (HSPD1) is a fitness gene and a potential target for NSCLC To understand whether HSPD1 could be an attractive target for NSCLC, we performed a fitness analysis from a previously published dataset of a pan-cancer and genome-wide CRISPR/Cas9 screening of 18,009 genes, which included n = 21 adenocarcinoma (ADC) and n = 11 squamous cell carcinoma (SqCC) cell lines [35]

  • We investigated the prevalence of HSPD1 expression in tissue samples from a small cohort of NSCLC patients (n = 30) by immunohistochemistry (IHC), and observed positive HSPD1 protein expression in 100% of the cases (Fig. 1F-I)

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Summary

Introduction

The identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Relapse and occurrence of treatmentresistant phenotypes are still very common, contributing to the current suboptimal scenario of 60 to 70% overall survival for early-stage and between 0 to 10% for patients carrying the advanced disease [5] This unsatisfactory picture strongly reinforces the need for developing new drugs targeting other fundamental lethal properties of lung cancer cells

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