Brain Metastases from Lung Cancer: Is MET an Actionable Target?

Abstract

The process of metastatic dissemination begins when malignant cells start to migrate and leave the primary mass. It is now known that neoplastic progression is associated with a combination of genetic and epigenetic events. Cancer is a genetic disease and this pathogenic concept is the basis for a new classification of tumours, based precisely on the presence of definite genetic lesions to which the clones are addicted. Regarding the scatter factor receptors MET and Recepteur d’Origin Nantais (RON), it is recognised that MET is an oncogene necessary for a narrow subset of tumours (MET-addicted) while it works as an adjuvant metastogene for many others. This notion highlights that the anti-MET therapy can be effective as the first line of intervention in only a few MET-addicted cases, while it is certainly more relevant to block MET in cases of advanced neoplasia that exploit the activation of the invasive growth program to promote dissemination in other body parts. Few data are instead related to the role played by RON, a receptor homologous to MET. We have already demonstrated an implication of MET and RON genes in brain metastases from lung cancer. On this basis, the aim of this work is to recapitulate and dissect the molecular basis of metastatic brain dissemination from lung cancer. The latter is among the big killers and frequently gives rise to brain metastases, most often discovered at diagnosis. Molecular mechanisms leading to tumour spread to the brain are mostly unknown and in turn these tragic cases are still lacking effective therapies. Based on previously published data from our group, we aim to summarise and analyse the pathogenic mechanisms leading to activation of the scatter factor receptor in brain metastatic lesions of lung primaries, from the point of view of replacing the currently used empirical treatment with a more targeted approach.

Stage 4 Lung Cancer with Brain and Pericardial Metastases Which Are First Considered as Pulmonary Tuberculosis Infection and Heart Failure

“…Due to an increase in intracranial pressure as well as the number, localisation, and rate of growth of brain metastases, they are associated with the onset of many clinical signs and symptoms, including headaches, sometimes with vomiting or nausea, seizure, cognitive disfunction and motoric disfunction. 20 In this case, patient felt weakness of his left hand for the last 3 months and brain CT scan showed hyperdense multiple nodul that suggesting of metastatic nodules.…”

Exploring the Mechanism of Inula japonica Thunb. against Non-small Cell Lung Cancer using a computer-aided drug design approach

“…Notably, NSCLC accounts for approximately 85%−90% of lung cancers [3]. The well-recognized pathogenic factors of NSCLC are tobacco consumption, air pollution, second-hand smoke exposure, occupational and environmental exposures, and genetic characteristics [4][5][6]. The most frequent clinical manifestations of NSCLC include chronic cough, bloody phlegm, chest pain, breathlessness, weight loss, metastasis pain, fatigue, fever, and respiratory distress [7], which seriously have impacts on human health, even life.…”

Brain penetration and efficacy of tepotinib in orthotopic patient-derived xenograft models of MET-driven non-small cell lung cancer brain metastases

“…Up to 40% of patients with NSCLC, overall, develop brain metastases during the course of the disease [13], and limited available data suggest a similarly high incidence in patients with METex14 skipping [14,15]. MET dysregulation has been implicated in the biology of metastasis to the central nervous system (CNS) [16], and MET amplification and/or overexpression are frequently observed in NSCLC brain lesions [17]. Patients with brain metastases have an especially poor prognosis, with short duration of overall survival [18,19].…”