Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR-tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma?

Zhang, Yan; Li, Xiaoyü; Tang, Yuan; Xu, Yong; Guo, Wenhao; Li, Yanchu; Liu, Xiaoke; Huang, Chuying; Wang, Yongsheng; Wei, Yuquan

doi:10.1016/j.lungcan.2013.04.005

Cited by 44 publications

(20 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the cell-fate transition might represent a mechanism for lung ADC developing resistance towards YAP-targeted therapy. In line with this, multiple reports also show that a phenotypic transition from ADC to small cell lung carcinoma (SCLC) promotes the drug resistance to EGFR tyrosine kinase inhibitors 47,48 . For these complicate diseases, tumour-type-specific and/or combinatory targeting strategies might be required to achieve more effective clinical outcomes for YAP-targeted therapy, especially to LKB1-mutant lung cancer.…”

Section: Discussionmentioning

confidence: 71%

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

et al. 2014

View full text Add to dashboard Cite

Whether the Hippo pathway contributes to cell lineage transition under pathological conditions, especially tumorigenesis, remains largely unknown. Here we show that YAP, the major effector of the Hippo pathway, displays a distinct activation pattern in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC); YAP is initially activated by LKB1 loss in lung ADC, which upregulates ZEB2 expression and represses DNp63 transcription in a default manner. During transdifferentiation, YAP is inactivated, which in turn relieves ZEB2-mediated default repression of DNp63 and triggers squamous differentiation reprogramming. Disruption of the YAP barrier for phenotypic transition significantly accelerates squamous transdifferentiation, whereas constitutive YAP activation conversely inhibits this transition. More importantly, ectopic DNp63 expression rescues the inhibitory effect of YAP on squamous transdifferentiation. These findings have established YAP as an essential barrier for lung cancer cell fate conversion and provided a mechanism for regulating cancer plasticity, which might hold important implication for YAP-targeted therapies.

show abstract

Section: Discussionmentioning

confidence: 71%

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

et al. 2014

View full text Add to dashboard Cite

show abstract

“…These conflicting findings suggest the possible existence of factors other than EGFR inhibition that might promote the transformation from EGFR-mutant adenocarcinoma to SCLC (46). In this case, in addition to the poor response to TKIs, the increased concentration of serum neuron-specific enolase, which rose from 17.9 ng/mL at the early stage of the disease to 211.10 ng/mL at the stage when progression was detected (reference range <15 ng/mL), could be a way to predict potential disease transformation (71).…”

Section: Mechanisms Of Acquired Resistance To Targeted Cancer Therapiesmentioning

confidence: 99%

“…Zhang et al (71) reported the case of an 80-year-old man with lung adenocarcinoma (stage IB) who had an EGFR mutation (deletion of exon 19). Second-line treatment with EGFR-TKI after progression failed, and the progression was accompanied by increased concentrations of the serum tumor marker neuron-specific enolase.…”

Section: Mechanisms Of Acquired Resistance To Targeted Cancer Therapiesmentioning

confidence: 99%

Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

Dorantes-Heredia¹,

Ruíz-Morales²,

Cano-García³

2016

Transl. Lung Cancer Res.

View full text Add to dashboard Cite

Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted therapies, histopathological transformation to small-cell lung carcinoma (SCLC) can occur in 3-15% of patients with non-small-cell lung carcinoma (NSCLC) tumors. By definition, SCLC is a high-grade tumor with specific histological and genetic characteristics. In the majority of cases, a good-quality hematoxylin and eosin (H&E) stain is enough to establish a diagnosis. Immunohistochemistry (IHC) is used to confirm the diagnosis and exclude other neoplasia such as sarcomatoid carcinomas, large-cell carcinoma, basaloid squamous-cell carcinoma, chronic inflammation, malignant melanoma, metastatic carcinoma, sarcoma, and lymphoma. A loss of the tumor-suppressor protein retinoblastoma 1 (RB1) is found in 100% of human SCLC tumors; therefore, it has an essential role in tumorigenesis and tumor development. Other genetic pathways probably involved in the histopathological transformation include neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1). Histological transformation to SCLC can be suspected in NSCLC patients who clinically deteriorate during active treatment. Biopsy of any new lesion in this clinical setting is highly recommended to rule out a SCLC transformation. New studies are trying to assess this histological transformation by noninvasive measures such as measuring the concentration of serum neuronspecific enolase.

show abstract

“…It is occasionally difficult to perform a second biopsy, and so NSE level may be useful for the early detection of transformation to SCLC in cases that are resistant to EGFR-TKI therapy. NSE could potentially overcome the limitations of performing biopsies on single lesions, which may miss the transformation of another metastatic lesion into SCLC (21)(22)(23)(24). It was concluded that a secondary biopsy was important for the evaluation of genetic and histological changes and the selection of an appropriate treatment following TKI resistance, and that NSE may be useful for the early detection of SCLC transformation.…”

Section: Discussionmentioning

confidence: 99%

Transformation to small‑cell lung cancer following treatment with icotinib in a patient with lung adenocarcinoma

Chen

Qin

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

Abstract. The present study describes the case of a 48-year-old man who was diagnosed with lung adenocarcinoma with an epidermal growth factor receptor (EGFR) 21 L858R mutation. The patient received surgery and adjuvant chemotherapy. When multiple lung metastases appeared, icotinib was administered. Following resistance to icotinib, biopsy by endobroncheal ultrasonography for a right lung hilar lymph node revealed transformation to a neuroendocrine morphology. Neuron-specific enolase (NSE) levels were elevated, accompanied with disease progression following transformation to the neuroendocrine morphology. The post-operative and biopsy specimens were analyzed for 416 genes using next-generation sequencing, and phosphatidylinositol-3-kinase catalytic α mutation and retinoblastoma loss were evident. Five cycles of etoposide combined with cisplatin were administered and a partial response was achieved. The disease progressed again accompanied with an elevated NSE level, and bronchoscopy examination revealed small cell lung cancer (SCLC) after 3 months. The patient received chemotherapy consisting of irinotecan combined with carboplatin for two cycles and achieved stable disease. Overall, a secondary biopsy is important for the evaluation of genetic and histological changes and the selection of an appropriate treatment following tyrosine kinase inhibitor (TKI) resistance, and NSE may be useful for the early detection of SCLC transformation in cases that are resistant to EGFR-TKI therapy. IntroductionLung cancer, including small-cell lung cancer (SCLC) and non-SCLC (NSCLC), which is mainly comprised of adenocarcinoma, squamous cell carcinoma and large cell carcinoma, is the most common type of malignancy and the leading cause of cancer-associated mortality worldwide (1). Adenocarcinoma is the most common type of NSCLC, and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy, including erlotinib, gefitinib or icotinib, is the gold standard of treatment for EGFR-mutant lung adenocarcinoma (2-4). The incidence of EGFR mutation in NSCLC in 2005 was higher in East Asian populations when compared with the incidence in other ethnicities (30 vs. 8%) (5). Patients with lung adenocarcinoma harboring exon 19 deletions achieved longer progression-free survival (PFS) and overall survival time (OS) compared with those with L858R mutations (6). However, patients ultimately develop acquired resistance, and the most recently identified mechanism for this is transformation to SCLC (7). Ahn et al (8) reported six cases of transformation from lung adenocarcinoma to SCLC. Erlotinib, gefitinib, afatinib and icotinib were equally as efficient as each other but exhibited different efficacy-toxicity patterns (4). EGFR-TKI-resistant SCLCs are differentiated early from the lung adenocarcinoma clones that harbor completely inactivated retinoblastoma 1 (RB1) and TP53 (9). Molecular mechanisms involved in the transformation from NSCLC to SCLC include TP53 mutations, RB1 loss, lack of EGFR expression and MYC amplificatio...

show abstract

Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR-tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma?

Cited by 44 publications

References 9 publications

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression

Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

Transformation to small‑cell lung cancer following treatment with icotinib in a patient with lung adenocarcinoma

Contact Info

Product

Resources

About