Oncogenic driver mutations in non-small cell lung cancer: Past, present and future

Lung cancer,of which non-small lung cancer is the most common subtype,represents the leading cause of cancer related-death worldwide.It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis.In recent years,more of these so-called oncogenic drivers have been identified,and a better understanding of their biology has allowed the development new targeted agents.This review aims to provide an update about the current landscape of driver mutation in non-smallcell lung cancer.Alterations in Kirsten rat sarcoma,epidermal growth factor receptor,MET,anaplastic lymphoma kinase,c-ROS oncogene 1,v-raf murine sarcoma viral oncogene homolog B,neurotrophic receptor tyrosine kinase,human epidermal growth factor 2,neuregulin-1 and rearranged during transfection are discussed,as well as agents targeting these alterations.Current standards of treatment as well as promising future strategies are presented.Currently,more than fifteen targeted agents are food and Drug administration-approved for seven oncogenic drivers in non-small-cell lung cancer,highlighting the importance of actively searching for these mutations.Continuous and future efforts made in defining the biology of each of these alterations will help to elucidate their respective resistance mechanisms,and to define the best treatment strategy and therapeutic sequence.

Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions

With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations (“target-dependent resistance”) and in the parallel and downstream pathways (“target-independent resistance”). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.

Near-Dead Cells to Special Tetraploidy to First Cells to Cancer Diagnostic Morphology: Unlikely Therapy-Gain from For-Profit Industrial Goliath

The objective in this experimental article is to gain evidential proof of near-dead cells, (sick-cells in relapse tumor) responding with recovery growth from special 4n, multi-chromatid chromosomes. Note, near-dead normal human cells with such converted chromosome structure gave rise to proliferative, fitness-gained, diploid first cells, which further gave rise to three different cell shape changed, recovery growth patterns. Previously, two cell shape changes had been recovered from same type normal human cells, transiently exposed to amino acid glutamine deficient growth medium with recovery growths also associated with presence of the special 4n cells. The 4n cell-division had been concluded to be a meiotic-like two-step division system to the fitness-gained diploid cells in numerous experiments. The main characteristics of this division system, was firstly whole genomes without polar oriented bent centromeres moving apart followed by much rarer simple fission division to two or three diploid cells, selectable for first cell proliferation. In general these 4n cells showed metaphase type rosette figures moving apart not in the normal spindle associated mitotic shape with centromeres polar-pointing with sloping arms. This sequence of events induced by glutamine-deficiency, was earlier shown to cause DNA breakage in metabolic studies however, the near-death condition was only assumed from normal fibro-blastic cell-sheet shrinkage. This was rectified by an RNA virus (Coxakie-B3), which virology known is a highly cell killing virus (4+ CPE on their scale). This virus replicates only in replicating cells, which led to recovery growths with progressive phenotypic cell-shape changes (spindle, polygonal and roundness cells), each intervened by “total” cell destruction. These three different growth patterns had morphologies, indistinguishably from today’s cancer diagnostic morphologies. “Mitotic” analyses of beginning growths for the three phenotypes revealed the special rosette figure separations from special 4n and higher ploidy level cells, and also total absence of spindle type mitoses. Tumorigenesis-relevant was centromere-puffing with premature chromatid separation, and chromatin compaction, a mechanism, that was suggested to protect the genome from damage (text). We suggest that the multi-chromatid polyploid cells with their genome reductive division system, can be a tractable in vitro model system for therapy information, when repeated from a cell-killing agent, producing virus-free recovery growths. Will it be enacted upon? Not likely with profit-greedy industrial Goliath in the helm of cancer research. But, a not for profit cancer organization, could change this appalling situation.

Molecular Therapeutics of Non-Small Cell Lung Cancer (NSCLC) and Challenges in Repeat Tissue Biopsy

With advances in targeted and personalized treatment for lung cancer, molecular analysis of tumors is routinely performed for sequencing of treatment options in patients with advanced non-small-cell lung cancer (NSCLC). Oncogene addiction due to driver mutations includes EGFR exon 20 insertion mutations, MET amplification, EML4-AL, KRAS G12C point mutations, RET rearrangements, HER2 amplification and mutations, and FGFR amplification and translocations. A re-biopsy at the time of tumor recurrence or progression after first-line treatment failure is important for further molecular assessment and personalized therapy. However, repeat tumor biopsies are fraught with challenges including access to the tumor, sample inadequacy, patient consent, patient performance status, safety, or physician’s choice or assessment. Cytological specimens are gaining importance but are limited due to validation difficulties. Liquid biopsies, which are minimally invasive have shown promise to assess dynamic biomarkers using ctDNA analysis and are thus frequently considered in routine clinical practice in advanced NSCLC patients to guide further targeted treatment. Here we present a comprehensive review that emphasizes the significance of performing tumor re-biopsy in advanced stage NSCLC patients following resistance to first-line treatment and simultaneously highlights the current challenges in performing the same and the current status and future perspectives of liquid biopsy in NSCLC.

Establishment and application of a multiplex genetic mutation-detection method of lung cancer based on MassARRAY platform

Objective: This study aims to establish a method for highly parallel multiplexed detection of genetic mutations in Chinese lung cancer samples through Agena i PLEX chemistry and matrix-assisted laser desorption ionization time-of-flight analysis on Mass ARRAY mass spectrometry platform.Methods: We reviewed the related literature and data on lung cancer treatments. We also identified 99 mutation hot spots in 13 target genes closely related to the pathogenesis, drug resistance, and metastasis of lung cancer. A total of 297 primers, composed of99 paired forward and reverse amplification primers and 99 matched extension primers, were designed using Assay Design software. The detection method was established by analyzing eight cell lines and six lung cancer specimens. The proposed method was then validated through comparisons by using a Lung Carta^(TM) kit. The sensitivity and specificity of the proposed method were evaluated by directly sequencing EGFR and KRAS genes in 100 lung cancer cases.Results: The proposed method was able to detect multiplex genetic mutations in lung cancer cell lines. This finding was consistent with the observations on previously reported mutations. The proposed method can also detect such mutations in clinical lung cancer specimens. This result was consistent with the observations with Lung Carta^(TM) kit. However, an FGFR2 mutation was detected only through the proposed method. The measured sensitivity and specificity were 100% and 96.3%, respectively.Conclusions: The proposed Mass ARRAY technology-based multiplex method can detect genetic mutations in Chinese lung cancer patients. Therefore, the proposed method can be applied to detect mutations in other cancer tissues.

Efficacy of ICIs on patients with oncogene-driven non-small cell lung cancer:a retrospective study

Aim:The objective of our study was to assess the efficacy of immune checkpoint inhibitors(ICIs)on patients with non-small-cell lung cancer(NSCLC)harboring oncogenic alterations.Methods:We retrospectively enrolled patients with advanced non-squamous NSCLC who were treated with anti-PD-1-based monotherapy or combined immunotherapy.Major characteristics including PD-L1 expression,treatment,and survival were analyzed.Results:In total,309 non-squamous NSCLC patients with a median age of 61 years(range 20-88 years)including 70.9%male were retrospectively enrolled.The molecular alterations involved epidermal growth factor receptor(EGFR)(n=81),V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(KRAS)(n=31),anaplastic lymphoma kinase(ALK)(n=1),human epidermal growth factor receptor 2(HER2)(n=12),V-raf murine sarcoma viral oncogene homolog(BRAF)(n=2),rearranged during transfection(n=4),and c-ros oncogene 1(ROS1)(n=3).In the EGFR subset,the ORR was 30.9%(n=81)and PFS was significantly shorter than WT group(median PFS:5.7 months vs.7.1 months;P=0.0061).In subgroup analyses,ICI combined therapy was significantly correlated with a longer PFS compared with ICI monotherapy(median PFS:7.7 months vs.4.7 months;P=0.0112).In KRAS patients,ORR was 51.6%(n=31).No significant difference was found in subgroup analyses.The ORR and PFS were 16.7%(n=12)and 28.6%(n=7),7.8 months and 9.0 months for HER2 and EGFR Exon20 insertion patients,respectively.Three ROS1 patients were enrolled with a PFS of 16.0,34.2,and 45.0 months individually,and one ALK patient with PFS of 4.4 months was identified.No response was found in two BRAF patients.Conclusion:ICI-based combination therapy can bring benefit to patients with EGFR-mutant NSCLC.ICI-based combination therapy could be considered for patients with ROS1 rearrangement,HER2 mutation and EGFR Exon20 insertion NSCLC.