Inherited lung cancer syndromes targeting never smokers

Abstract

Lung cancer is the leading cause of cancer death worldwide. Most of lung cancers develop sporadically and thus inherited lung cancers are rare. Several reports show that germline mutations in the kinase domain of epidermal growth factor receptor () such as R776G, R776H, T790M, V843I and P848L, predispose to develop lung cancer. Most lung cancer cases with germline T790M mutations had secondary somatic mutations. Never smokers with germline T790M mutations develop lung cancer more frequently than ever smokers. In addition, germline T790M mutations favored female gender. Therefore, germline T790M mutations result in a unique inherited lung cancer syndrome targeting never smokers. The authors previously reported a Japanese familial lung cancer pedigree with germline mutations in the transmembrane domain of human epidermal growth factor receptor 2 (). The female proband and her mother in this pedigree, who were light or never smokers, developed multiple lung adenocarcinomas, and had germline G660D mutations. They had no somatic mutations or other genes known to cause lung cancers. Although we know only one pedigree with germline mutations, these mutations may also cause inherited lung cancers targeting female never smokers. Based on our analyses, we administered inhibitor afatinib to the proband and achieved partial response. These lung cancers arising from germline mutations of receptor tyrosine kinases such as and may have different features from those with sporadic mutations.

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

“…In addition to somatic mutations, other reported EGFR-associated mechanisms for inherent resistance to EGFR-TKIs are the germline T790M polymorphism in exon 20 and the germline V843I mutation in exon 21 [113,114,115]. NSCLCs with germline T790M or V843I mutations are predominantly LACs harboring a secondary somatic classic EGFR -mutation and occur more frequently in females and non-smokers [115]. The families harboring the T790M or V843I mutations are predisposed to NSCLC development as these mutations contribute to tumorigenesis by promoting phosphorylation of EGFR and its downstream signaling proteins.…”

“…Like T790M, the V843I mutation is associated with familial clustering of NSCLC and appears to provide resistance to EGFR-TKIs through structural modification of EGFR that sterically hinders TKI binding [113,114]. Thus, cases with germline T790M or V843I mutations could be categorized as a class of familial lung cancer syndrome with resistance to 1G/2G EGFR-TKIs but possibly sensitive to 3G TKIs [114,115].…”

Treatment and Prevention of Lung Cancer Using a Virus-Infected Reprogrammed Somatic Cell-Derived Tumor Cell Vaccination (VIReST) Regime

“…In this study, we showed that KP-LC vaccine evokes anti-tumor T cell responses using both subcutaneous tumor and induced transgenic models of disease ( Figure 6A ) and significantly extended the survival time of KP-LC vaccinated mice, although notably did not prevent disease related death. This suggests scope for improvement of the regime, that should include optimizing the number of prime-boost cycles applied to the patient and more specific tailoring of iPSCs by introduction of other driver mutations, particularly those associated with genetic inheritance, including EGFR amongst others ( 37 ). It is worth noting that vaccination produced by the lung cancer cell line KP-LC derived from iPS cells or the lung cancer cell line KPL 160302S derived from early lung cancer models can both significantly prolong the survival of lung cancer mice, and their effect on CD8+ T cells and CD4+ T cells infiltration are similar.…”

Patients with advanced non‑small cell lung cancer with EGFR mutations in addition to complex mutations treated with osimertinib have a poor clinical outcome: A real‑world data analysis

“…There are numerous other EGFR-related mutations associated with resistance mechanisms, such as the EGFR P848L mutation ( 18 – 22 ), EGFR amplification ( 23 , 24 ), MET amplification ( 25 , 26 ), HER2 mutations ( 27 , 28 ), PIK3CA mutations ( 29 – 31 ) and mutations activating the RAS-MAPK signalling pathway ( 32 – 35 ). The present study revealed that a patient with the EGFR21L858R, P848L/T790M mutations experienced rapid progression after TKI treatment, including osimertinib.…”