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Abstract   Background  Lung cancer is the primary cause of cancer deaths worldwide. Activation of epidermal growth factor receptor (EGFR) leads to lung cancer progression and poor prognosis while involuntary weight loss remains a major problem. Tumour‐derived parathyroid hormone‐related protein (PTHrP) emerged as a potential mediator of cachexia. Here, we investigated the modulatory role of EGFR signalling in PTHrP (encoded by  Pthlh ) gene expression and the impact of this relationship on cancer cachexia.    Methods  Global gene expression profiles of Lewis lung carcinoma (LLC) cells were analysed.  Pthlh  mRNA levels were measured by qRT‐PCR in LLC cells treated with EGFR ligands and tyrosine kinase inhibitors (TKIs). LLC tumour‐bearing mice received EGFR TKI erlotinib for 7 days via intraperitoneal injection or oral gavage. Tumour  Pthlh  mRNA, weight of fat/muscle tissue, and grip strength were assessed. RNA‐seq data from The Cancer Genome Atlas and gene expression analysis tools were used to characterize expression profiles of  PTHLH  and  EGFR  along with correlation analysis of  PTHLH  with  EGFR  and transforming growth factor alpha ( TGFA ) in human lung cancer and head and neck squamous carcinoma (HNSC). Survival of lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) patients with EGFR gene alterations was analysed in regard to  PTHLH  expression.    Results  Expression of EGFR ligands, EGFR itself, and PTHrP co‐clusters in LLC cells. Activation of EGFR signalling with its ligands significantly increases (3.8‐fold,  P  &lt; 0.0005) while EGFR TKIs significantly decrease (90%,  P  &lt; 0.0005)  Pthlh  mRNA levels in LLC cells.  Pthlh  mRNA drops 65–75% ( P  &lt; 0.0005) in tumours upon treatment of LLC tumour‐bearing mice with erlotinib while their muscle mass and grip strength increase (9.2%  P  &lt; 0.05, 23%  P  &lt; 0.005, respectively) compared with tumour‐bearing control mice.  PTHLH  is overexpressed in tumours of LUSC (45.8‐fold,  P  &lt; 0.05) and HNSC (17.5‐fold,  P  &lt; 0.05) compared with normal tissue.  PTHLH  expression correlates with  EGFR  and its ligand  TGFA  in both cancers (LUSC:  n  = 745,  R  = 0.32,  P  &lt; 0.0001 and  R  = 0.51,  P  &lt; 0.0001; HNSC:  n  = 545,  R  = 0.34,  P  &lt; 0.001 and  R  = 0.50,  P  &lt; 0.001, respectively). High  PTHLH  mRNA associates with poor overall survival in LUAD patients with activating EGFR mutations ( n  = 40, log‐rank test,  P  = 0.0451).    Conclusions  Epidermal growth factor receptor signalling regulates expression of cachexia mediator PTHrP. EGFR inhibition reduces PTHrP expression in LLC tumours and ameliorates cachexia in LLC tumour‐bearing mice.

journal of cachexia, sarcopenia and muscle

Inhibition of epidermal growth factor receptor suppresses parathyroid hormone‐related protein expression in tumours and ameliorates cancer‐associated cachexia