The rapid evolution of treatment for advanced lung cancer is a story of how scientists have struggled to move from nonselective cytotoxic chemotherapy to personalized precision medicine. In this ...century, extraordinary advances have been made in the management of advanced and metastatic non-small cell lung cancer, especially in the development of small molecules targeting specific tyrosine kinase receptors and immune checkpoint inhibitors. These developments have led to a significant improvement in survival for lung cancer patients with metastatic disease. Now, the core guidelines to treat non-small cell lung cancer are based on the identification of targetable driver mutations and immune checkpoints. Continued investigations of newly identified druggable genetic alterations, explorations of biomarkers of immune checkpoint inhibitors, development of next-generation immunotherapy, and optimization of combination therapy are necessary to provide better treatment outcomes for lung cancer patients in the future.
Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non-small cell lung cancer (NSCLC) are well known. The ...clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance.
Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations.
Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months).
Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed.
Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations have excellent response to EGFR tyrosine kinase inhibitors (TKIs), but T790M ...mutation accounts for most TKI drug resistance. This study used highly sensitive methods to detect T790M before and after TKI therapy and investigated the association of T790M and its mutation frequencies with clinical outcome.
Direct sequencing, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and next-generation sequencing (NGS) were used to assess T790M in the following two cohorts of patients with NSCLC: TKI-naive patients (n = 107) and TKI-treated patients (n = 85). Results were correlated with TKI treatment response and survival.
MALDI-TOF MS was highly sensitive in detecting and quantifying the frequency of EGFR-activating mutations and T790M (detection limits, 0.4% to 2.2%). MALDI-TOF MS identified more T790M than direct sequencing in TKI-naive patients with NSCLC (27 of 107 patients, 25.2% v three of 107 patients, 2.8%, respectively; P < .001) and in TKI-treated patients (before TKI: 23 of 73 patients, 31.5% v two of 73 patients, 2.7%, respectively; P < .001; and after TKI: 10 of 12 patients, 83.3% v four of 12 patients, 33.3%, respectively; P = .0143). The EGFR mutations and their frequencies were confirmed by NGS. T790M was an independent predictor of decreased progression-free survival (PFS) in patients with NSCLC who received TKI treatment (P < .05, multivariate Cox regression).
T790M may not be a rare event before or after TKI therapy in patients with NSCLC with EGFR-activating mutations. The pretreatment T790M mutation was associated with shorter PFS with EGFR TKI therapy in patients with NSCLC.
Netrin-1 is upregulated in a large fraction of human neoplasms. In multiple animal models, interference with netrin-1 is associated with inhibition of tumor growth and metastasis. Although netrin-1 ...upregulation was initially described in cancer cells, we report here that in the human colorectal cancer database, the expression of netrin-1 and its receptor UNC5B correlates with a cancer-associated fibroblasts (CAF) signature. Both colon and lung CAF secreted netrin-1 when cocultured with respective cancer cells, and netrin-1 upregulation in CAF was associated with increased cancer cell stemness. Pharmacologic inhibition of netrin-1 with a netrin-1-mAb (Net1-mAb) abrogated the CAF-mediated increase of cancer stemness both in coculture experiments and in mice. Net-1-mAb inhibited intercellular signaling between CAF and cancer cells by modulating CAF-mediated expression of cytokines such as IL6. Together these data demonstrate that netrin-1 is upregulated not only in cancer cells but also in cancer-associated stromal cells. In addition to its direct activity on cancer cells, inhibition of netrin-1 may reduce proneoplastic CAF-cancer cell cross-talk, thus inhibiting cancer plasticity. SIGNIFICANCE: Netrin-1, a navigation cue during embryonic development, is upregulated in cancer-associated fibroblasts and regulates cancer cell stemness.
PIONEER (NCT01185314) was a prospective, multinational, epidemiological study of epidermal growth factor receptor (EGFR) mutations in patients from Asia with newly diagnosed advanced lung ...adenocarcinoma.
Eligible patients (aged ≥20 years) had untreated stage IIIB/IV adenocarcinoma. The EGFR mutation status (primary end point: positive, negative, or undetermined) of tumor samples (biopsy, surgical specimen, or cytology) was determined (Scorpion amplification refractory mutation system). EGFR mutation frequency was calculated and compared between demographic and clinical subgroups.
Of 1482 patients from seven Asian regions, 43.4% of patients were female, median age was 60 years (range, 17–94), and 52.6% of patients were never-smokers. EGFR mutation status was evaluable in tumors from 1450 patients (97.8%) (746 51.4% positive; 704 48.6% negative). Country, sex, ethnicity, smoking status, pack-years (all p < 0.001), disease stage (p = 0.009), and histology type (p = 0.016) correlated significantly with EGFR mutation frequency. Mutation frequency was 61.1% in females, 44.0% in males; lower in patients from India (22.2%) compared with other areas (47.2%–64.2%); highest among never-smokers (60.7%); and decreased as pack-year number increased (>0–10 pack-years, 57.9%; >50 pack-years, 31.4%) (similar trend by sex). Ethnic group (p < 0.001) and pack-years (p < 0.001) had statistically significant associations with mutation frequency (multivariate analysis); sex was not significant when adjusted for smoking status.
PIONEER is the first prospective study to confirm high EGFR mutation frequency (51.4% overall) in tumors from Asian patients with adenocarcinoma. The observed high mutation frequency in demographic/clinical subgroups compared with white populations suggests that mutation testing should be considered for all patients with stage IIIB/IV adenocarcinoma, even males and regular smokers, among Asian populations.
Lung cancer is the leading cause of cancer death worldwide. Cancer metastasis and resistance to treatment (including radiotherapy, chemotherapy and targeted therapy) are two major causes for the poor ...survival of lung cancer patients. Epithelial-mesenchymal transition (EMT) is involved in cancer cell invasion, resistance to apoptosis and stem cell features. The process of EMT is controlled by a group of transcriptional factors, zinc finger proteins and basic helix-loop-helix factors. Signaling pathways activated by intrinsic or extrinsic stimuli converge on these transcriptional factors and regulated the phenotypic changes of cancer cells. These EMT regulators may play an important role in cancer progression. In lung cancer, Slug is the most thoroughly investigated EMT regulator. The expression of Slug is associated with lung cancer invasion and resistance to target therapy. In this review, we focus on the current understanding of the role of Slug in the carcinogenesis and progression of lung cancer.
ENO1 (α-enolase) expression is significantly correlated with reduced survival and poor prognosis in many cancer types, including lung cancer. However, the function of ENO1 in carcinogenesis remains ...elusive. In this study, we found that high expression of ENO1 is present in metastatic lung cancer cell lines and malignant tumors and is associated with poor overall survival of patients with lung cancer. Knockdown of ENO1 decreased cancer cell proliferation and invasiveness, whereas overexpression of ENO1 enhanced these processes. Moreover, ENO1 expression promoted tumor growth in orthotopic models and enhanced lung tumor metastasis in tail-vein injection models. These effects were mediated by upregulation of mesenchymal markers N-cadherin and vimentin and the epithelial-to-mesenchymal transition regulator SLUG, along with concurrent downregulation of E-cadherin. Mechanistically, ENO1 interacted with hepatocyte growth factor receptor (HGFR) and activated HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt coreceptor LRP5/6. Activation of these signaling axes decreased GSK3β activity via Src-PI3K-AKT signaling and inactivation of the β-catenin destruction complex to ultimately upregulate SLUG and β-catenin. In addition, we generated a chimeric anti-ENO1 mAb (chENO1-22) that can decrease cancer cell proliferation and invasion. chENO1-22 attenuated cancer cell invasion by inhibiting ENO1-mediated GSK3β inactivation to promote SLUG protein ubiquitination and degradation. Moreover, chENO1-22 prevented lung tumor metastasis and prolonged survival in animal models. Taken together, these findings illuminate the molecular mechanisms underlying the function of ENO1 in lung cancer metastasis and support the therapeutic potential of a novel antibody targeting ENO1 for treating lung cancer. SIGNIFICANCE: This study shows that ENO1 promotes lung cancer metastasis via HGFR and WNT signaling and introduces a novel anti-ENO1 antibody for potential therapeutic use in lung cancer.
Precision medicine is becoming the standard of care in anti-cancer treatment. The personalized precision management of cancer patients highly relies on the improvement of new technology in next ...generation sequencing and high-throughput big data processing for biological and radiographic information.Systemic precision cancer therapy has been developed for years. However, the role of precision medicine in radiotherapy has not yet been fully implemented. Emerging evidence has shown that precision radiotherapy for cancer patients is possible with recent advances in new radiotherapy technologies, panomics, radiomics and dosiomics.This review focused on the role of precision radiotherapy in non-small cell lung cancer and demonstrated the current landscape.
Abstract Background Programmed cell death-ligand 1 (PD-L1) is expressed in a subgroup of lung cancer that may benefit from immunotherapy. The interaction between PD-L1 expression and tumour ...infiltrating lymphocytes (TIL) remains poorly understood. This study investigated the expression of PD-L1 in surgically resected stage I pulmonary squamous cell carcinoma (SqCC) and correlated it with TILs in tumour microenvironments, common driver mutations, and clinical outcomes. Materials and methods One hundred and five patients with surgically resected stage I squamous cell carcinoma were examined. Paraffin-embedded tumour sections were stained with PD-L1 antibody. Tumours with moderate-to-strong membrane staining in ≥5% of tumour cells were scored as positive for PD-L1 expression. The driver mutation epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and v-raf murine sarcoma viral oncogene homolog B (BRAF) were examined by direct sequencing, while anaplastic lymphoma kinase (ALK), phosphoinositide 3-kinase catalytic alpha (PI3KCA), and fibroblast growth factor receptor 1 (FGFR1) were analysed by immunohistochemistry. The correlations of PD-L1 expression with each subtype of TIL, driver mutations, clinicopathologic parameters, and clinical outcomes were analysed. Results There was positive PD-L1 expression in 56.2% (59/105) of patients. PD-L1 expression was not associated with the common clinicopathologic features and mutations of EGFR, KRAS, BRAF, ALK, PI3KCA, and FGFR1. As regards TILs composition, tumour PD-L1 expression was significantly associated with increased tumour epithelial CD8+ T cells and stromal CD4+ T cells. Otherwise, PD-L1 (+) tumour cells were negatively correlated with PD-L1 (+) immune cells within tumour stroma. By multivariate analysis, tumour PD-L1 expression and increased CD4+ T cell infiltrations in the tumour stroma were independent predictors of better overall survival and had a trend of better disease-free survival. Conclusions PD-L1 expression is associated with a favourable immune microenvironment in stage I pulmonary SqCC and correlates with better clinical outcome.
Macrophages in a tumor microenvironment have been characterized as M1- and M2-polarized subtypes. Here, we discovered the different macrophages' impacts on lung cancer cell A549. The M2a/M2c subtypes ...promoted A549 invasion and xenograft tumor growth. The M1 subtype suppressed angiogenesis. M1 enhanced the sensitivity of A549 to cisplatin and decreased the tube formation activity and cell viability of A549 cells by inducing apoptosis and senescence. Different macrophage subtypes regulated genes involved in the immune response, cytoskeletal remodeling, coagulation, cell adhesion, and apoptosis pathways in A549 cells, which was a pattern that correlated with the altered behaviors of the A549 cells. Furthermore, we found that the identified M1/M2 gene signatures were significantly correlated with the extended overall survival of lung cancer patients. These results suggest that M1/M2 gene expression signature may be used as a prognostic indicator for lung cancer patients, and M1/M2 polarization may be a target of investigation of immune-modulating therapies for lung cancer in the future.
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