REST Inactivation and Coexpression of ASCL1 and POU3F4 Are Necessary for the Complete Transformation of RB1/TP53-Inactivated Lung Adenocarcinoma into Neuroendocrine Carcinoma

Masawa, Meitetsu; Sato-Yazawa, Hanako; Kashiwagi, Kunihiro; Ishii, Jun; Miyata-Hiramatsu, Chie; Iwamoto, Masami; Kohno, Kakeru; Miyazawa, Tadasuke; Onozaki, Masato; Noda, Shuhei; Shimizu, Yasuo; Niho, Seiji; Yazawa, Takuya

doi:10.1016/j.ajpath.2022.03.007

Cited by 7 publications

(3 citation statements)

References 42 publications

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“…Furthermore, we determined the expression of REST in A549 cells. A549 cells were selected to express high levels of REST ( 35 ). For functional analysis of ASO, we employed the REST-targeted ASO (REST_ASO) developed in our laboratory.…”

Section: Resultsmentioning

confidence: 99%

A novel transient receptor potential C3/C6 selective activator induces the cellular uptake of antisense oligonucleotides

Kohashi,

Nagata,

Tamenori

et al. 2024

Nucleic Acids Research

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Antisense oligonucleotide (ASO) therapy is a novel therapeutic approach in which ASO specifically binds target mRNA, resulting in mRNA degradation; however, cellular uptake of ASOs remains critically low, warranting improvement. Transient receptor potential canonical (TRPC) channels regulate Ca2+ influx and are activated upon stimulation by phospholipase C-generated diacylglycerol. Herein, we report that a novel TRPC3/C6/C7 activator, L687, can induce cellular ASO uptake. L687-induced ASO uptake was enhanced in a dose- and incubation-time-dependent manner. L687 enhanced the knockdown activity of various ASOs both in vitro and in vivo. Notably, suppression of TRPC3/C6 by specific siRNAs reduced ASO uptake in A549 cells. Application of BAPTA-AM, a Ca2+ chelator, and SKF96365, a TRPC3/C6 inhibitor, suppressed Ca2+ influx via TRPC3/C6, resulting in reduced ASO uptake, thereby suggesting that Ca2+ influx via TRPC3/C6 is critical for L687-mediated increased ASO uptake. L687 also induced dextran uptake, indicating that L687 increased endocytosis. Adding ASO to L687 resulted in endosome accumulation; however, the endosomal membrane disruptor UNC7938 facilitated endosomal escape and enhanced knockdown activity. We discovered a new function for TRPC activators regarding ASO trafficking in target cells. Our findings provide an opportunity to formulate an innovative drug delivery system for the therapeutic development of ASO.

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Section: Resultsmentioning

confidence: 99%

A novel transient receptor potential C3/C6 selective activator induces the cellular uptake of antisense oligonucleotides

Kohashi,

Nagata,

Tamenori

et al. 2024

Nucleic Acids Research

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“…Finally, secondary gene alterations appear in the process of transformation, including RB1 loss, TP53 mutation, and PIK3CA and BRAF mutation. Recent studies have revealed some novel gene alterations that are associated with the course of transformation, which include WNK1 mutation (Yu et al 2022), SPP1 upregulation (Z. , REST inactivation (Masawa et al 2022), and ETV1 mutation (Zhou et al 2021). In addition, Xie et al reported that the conversion of LUAD to SCLC may result from somatic copy number variation (CNV) events rather than from mutational events.…”

Section: Discussionmentioning

confidence: 99%

Etoposide/platinum plus anlotinib for patients with transformed small-cell lung cancer from EGFR-mutant lung adenocarcinoma after EGFR-TKI resistance: A retrospective and observational study

Ding

Leng

Gu³

et al. 2023

Preprint

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Objective: The histological conversion of lung adenocarcinoma (LUAD) into small-cell lung cancer (SCLC) is an important resistance mechanism for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant LUAD. Anlotinib has been recommended as the third-line treatment for SCLC patients. The efficacy of etoposide/platinum (EP) as the main treatment is very limited for patients with transformed SCLC. However, little is known about EP plus anlotinib for transformed SCLC. The present study retrospectively explored the clinical response to EP combined with anlotinib in patients with transformed SCLC from LUAD after EGFR-TKI failure. Methods: A total of 10 patients who underwent SCLC transformation from EGFR-TKI-resistant LUAD were retrospectively reviewed from September 1, 2019, to December 31, 2022, in three regional hospitals. All of the patients were treated with the combination regimen of EP and anlotinib for four to six cycles, followed by anlotinib maintenance therapy. The clinical efficacy indices including objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and toxicities were evaluated. Results: The median time from EGFR-TKI treatment to SCLC conversion was 20.1±2.76 months (17–24 months). Genetic examination after transformation showed that 90% of the patients retained their original EGFR gene mutations. Additional driver genes included BRAF mutation (10%), PIK3CA mutation (20%), RB1 loss (50%), and TP53 mutation (60%). The ORR and DCR were 80% and 100%, respectively. The mPFS was 9.0 months (95% CI, 7.9–10.1 months), and the mOS was 14.0 months (95% CI, 12.0–15.9 months). Less than 10% of grade 3 toxicities were observed, and no grade 4 toxicity and death events were reported. Conclusion: The EP plus anlotinib regimen appears to be a promising and safe strategy in transformed SCLC patients after EGFR-TKI resistance, which warrants further investigation.

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“…Histological transformation of lung cancer was first reported in a female NSCLC patient with EGFR exon 19 deletion, who converted into SCLC after gefitinib resistance in 2006 (21). For EGFR-mutant NSCLC transformation into SCLC, there are many responsible additional gene alterations, such as RB1 loss, TP53 mutations, PIK3CA, BRAF, WNK1, and ETV1 mutations, SPP1 upregulation, and REST inactivation (22)(23)(24)(25)(26)(27)(28)(29). Notably, the status of RB1 loss and TP53 mutations in EGFR TKI-treated NSCLC have One is the selection doctrine of combined ingredients, i.e., that the initial tumor comprises NSCLC and SCLC components.…”

Section: Potential Mechanisms For Histological Transformation From Ns...mentioning

confidence: 99%

Histological transformation into SCLC: An important resistance mechanism of NSCLC upon immunotherapy

Zeng,

Ding,

Ding

et al. 2023

Front. Immunol.

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The phenomenon of histological transformation has been widely reported in advanced non-small cell lung cancer (NSCLC) with EGFR mutations following the failure of EGFR-TKI treatment. Recent evidence suggests that similar histological changes can also occur in advanced NSCLC without driver gene mutations after developing resistance to immunotherapy. In this review, it was found that 66.7% of cases with immunotherapy-induced histological transformation were classified as lung squamous cell carcinoma (LSCC), while histological conversion into lung adenocarcinoma (LUAD) without EGFR or ALK gene mutations has rarely been reported. There have been sporadic reports on the occurrence of mutual transformation between LUAD and LSCC. The histological conversion from NSCLC into small cell lung cancer (SCLC) appears to be significantly underestimated, likely due to the infrequency of re-biopsy following the development of immunotherapy resistance. Several studies have reported a close association between the transformation and mutations at TP53 and the RB1 splice site, as well as the loss of an FBXW7 mutation. However, the exact mechanisms underlying this conversion remain unclear. Currently, there is a lack of guidelines for the management of transformed SCLC from NSCLC following immunotherapy, with chemotherapy being the most commonly employed treatment approach.

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REST Inactivation and Coexpression of ASCL1 and POU3F4 Are Necessary for the Complete Transformation of RB1/TP53-Inactivated Lung Adenocarcinoma into Neuroendocrine Carcinoma

Cited by 7 publications

References 42 publications

A novel transient receptor potential C3/C6 selective activator induces the cellular uptake of antisense oligonucleotides

A novel transient receptor potential C3/C6 selective activator induces the cellular uptake of antisense oligonucleotides

Etoposide/platinum plus anlotinib for patients with transformed small-cell lung cancer from EGFR-mutant lung adenocarcinoma after EGFR-TKI resistance: A retrospective and observational study

Histological transformation into SCLC: An important resistance mechanism of NSCLC upon immunotherapy

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