Small-cell transformation of <i>ALK</i>-rearranged non-small-cell adenocarcinoma of the lung

Balla, Agnes; Khan, Fatima; Hampel, Kenneth J; Aisner, Dara L.; Sidiropoulos, Nikoletta

doi:10.1101/mcs.a002394

Cited by 25 publications

(16 citation statements)

References 14 publications

(18 reference statements)

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“…To the best of our knowledge, this is the rst time that an incidence of transformation in the EGFR wild type NSCLCs was reported. The majority of previous studies focused on EGFR mutant patients, only several individual cases reported the SCLC transformation from EGFR wild-type NSCLC [3,[17][18][19]. In our cohort consisting of 591 EGFR wild type patients, 11 transformed cases were identi ed in 113 individuals with repeat biopsy (11/113, 9.73%).…”

Section: Discussionmentioning

confidence: 95%

Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer

Ding

Shi

Liu

et al. 2022

Preprint

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Background Histological transformation to small cell lung cancer (SCLC) has been identified as a mechanism of TKIs resistance in EGFR-mutant non-small cell lung cancer (NSCLC). However, the prevalence of transformation in EGFR-wildtype NSCLC and the mechanism are rarely understood. Methods We reviewed 1474 NSCLC patients to investigate the NSCLC-to-SCLC transformed cases and the basic clinical characteristics, driver gene status and disease course of them. To explore the potential functional genes in SCLC transformation, we obtained pre- and post-transformation specimens and subjected them to a multigene NGS panel involving 416 cancer-related genes. To validate the putative gene function, we established knocked-out models by CRISPR-Cas 9 in HCC827 and A549-TP53-/- cells and investigated the effects on tumor growth, drug sensitivity and neuroendocrine phenotype in vitro and in vivo. We also detected the expression level of protein and mRNA to explore the molecular mechanism involved. Results We firstly reported an incidence rate of 9.73% (11/113) of SCLC transformation in EGFR-wildtype NSCLC and demonstrated that SCLC transformation is irrespective of EGFR mutation status (P = 0.16). We sequenced 8 paired tumors and identified a series of mutant genes specially in transformed SCLC such as SMAD4, RICTOR and RET. We knocked out SMAD4 and RB1 in TP53-deficient NSCLC cells and firstly demonstrated that SMAD4 deficiency can accelerate SCLC transition by inducing neuroendocrine phenotype regardless of RB1 status. Further mechanical experiments identified the SMAD4 can regulate ASCL1 transcription competitively with Myc in NSCLC cells and Myc inhibitor acts as a potential subsequent treatment agent. Conclusions Transformation to SCLC is irrespective of EFGR status and can be accelerated by SMAD4 in non-small cell lung cancer. Myc inhibitor acts as a potential therapeutic drug for SMAD4-mediated resistant lung cancer.

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Section: Discussionmentioning

confidence: 95%

Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer

Ding

Shi

Liu

et al. 2022

Preprint

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“…Gene mutations retrieved from ClinVar. Gene name, accession number, mutation, clinical significance and literature references are reported, respectivelyGeneAccessionMutationClinical significanceRefEGFRNM_005228.4(EGFR)c.2573T>G (p.Leu858Arg)Pathogenic-drug response([61])ERBB2NM_001005862.2(ERBB2)c.2223_2234dupATACGTGATGGCPathogenic/Likely pathogenic([62])(p.Ala745_Gly746insTyrValMetAla)ALKNM_004304.4(ALK)c.3522C>A (p.Phe1174Leu)Pathogenic/Likely pathogenic([63])PTENNM_000314.6(PTEN)c.697C>T (p.Arg233Ter)Pathogenic([64])KRASNM_004985.4(KRAS)c.437C>T (p.Ala146Val)([65])BRAFNM_004333.5(BRAF)c.1794_1796dup (p.Thr599_Val600insThr)Pathogenic-drug response([66])PI3KNM_006218.3(PIK3CA)c.3140A>G (p.His1047Arg)Pathogenic/Likely pathogenic([67, 68])AKT1NM_005163.2(AKT1)c.49G>A (p.Glu17Lys)Pathogenic/Likely pathogenic([69, 70])MEK/MAP2K1NM_002755.3(MAP2K1)c.167A>C (p.Gln56Pro)Pathogenic([71, 72])EML4-ALK-p16chr2:29446394..42552694 inversionPathogenic([73])…”

Section: Methodsmentioning

confidence: 99%

MiRNA therapeutics based on logic circuits of biological pathways

et al. 2019

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BackgroundIn silico experiments, with the aid of computer simulation, speed up the process of in vitro or in vivo experiments. Cancer therapy design is often based on signalling pathway. MicroRNAs (miRNA) are small non-coding RNA molecules. In several kinds of diseases, including cancer, hepatitis and cardiovascular diseases, they are often deregulated, acting as oncogenes or tumor suppressors. miRNA therapeutics is based on two main kinds of molecules injection: miRNA mimics, which consists of injection of molecules that mimic the targeted miRNA, and antagomiR, which consists of injection of molecules inhibiting the targeted miRNA. Nowadays, the research is focused on miRNA therapeutics. This paper addresses cancer related signalling pathways to investigate miRNA therapeutics.ResultsIn order to prove our approach, we present two different case studies: non-small cell lung cancer and melanoma. KEGG signalling pathways are modelled by a digital circuit. A logic value of 1 is linked to the expression of the corresponding gene. A logic value of 0 is linked to the absence (not expressed) gene. All possible relationships provided by a signalling pathway are modelled by logic gates. Mutations, derived according to the literature, are introduced and modelled as well. The modelling approach and analysis are widely discussed within the paper. MiRNA therapeutics is investigated by the digital circuit analysis. The most effective miRNA and combination of miRNAs, in terms of reduction of pathogenic conditions, are obtained. A discussion of obtained results in comparison with literature data is provided. Results are confirmed by existing data.ConclusionsThe proposed study is based on drug discovery and miRNA therapeutics and uses a digital circuit simulation of a cancer pathway. Using this simulation, the most effective combination of drugs and miRNAs for mutated cancer therapy design are obtained and these results were validated by the literature. The proposed modelling and analysis approach can be applied to each human disease, starting from the corresponding signalling pathway.

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“…Although strongly associated with smoking, SCLC may also transform from a non–small cell lung carcinoma (NSCLC) as a resistance mechanism after targeted tyrosine kinase inhibitor therapy for EGFR , ALK , or ROS1 -mutated NSCLC 8–11…”

Section: Small Cell Lung Carcinomamentioning

confidence: 99%

Small Biopsy and Cytology of Pulmonary Neuroendocrine Neoplasms: Brief Overview of Classification, Immunohistochemistry, Molecular Profiles, and World Health Organization Updates

Sung

Heymann

Politis

et al. 2022

Advances in Anatomic Pathology

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Pulmonary neuroendocrine neoplasms comprise ~20% of all lung tumors. Typical carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma represent the 4 major distinct subtypes recognized on resections. This review provides a brief overview of the cytomorphologic features and the 2021 World Health Organization classification of these tumor types on small biopsy and cytology specimens. Also discussed are the role of immunohistochemistry in the diagnosis and molecular signatures of pulmonary neuroendocrine tumors.

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Small-cell transformation of ALK-rearranged non-small-cell adenocarcinoma of the lung

Cited by 25 publications

References 14 publications

Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer

Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer

MiRNA therapeutics based on logic circuits of biological pathways

Small Biopsy and Cytology of Pulmonary Neuroendocrine Neoplasms: Brief Overview of Classification, Immunohistochemistry, Molecular Profiles, and World Health Organization Updates

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