Evolution and genotypic characteristics of small cell lung cancer transformation in non-small cell lung carcinomas

Zhong, Jia; Li, Xiaoting; Wang, Zhijie; Duan, Jianchun; Li, Wenbin; Zhuo, Minglei; An, Tongtong; Wang, Ziping; Gu, Tiantian; Wang, Yuyan; Bai, Hua; Wang, Yan; Wu, Meina; Zhao, Zhikun; Yang, Xin; Su, Zhe; Zhu, Xiang; Wan, Rui; Li, Jianjie; Zhao, Jie; Chang, Geyun; Yang, Xue; Chen, Hanxiao; Xue, Liang; Shi, Xiaohua; Zhao, Jun; Wang, Jie

doi:10.1016/j.jncc.2021.11.001

Cited by 4 publications

(6 citation statements)

References 42 publications

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“…EGFR inhibition leads to a transient increase in A3A and A3B expression and APOBEC deaminase activity. This mirrors clinical data that shows an increase in the APOBEC mutational signature in tumors from patients who have acquired resistance to an EGFR inhibitor, especially those with tumors that have undergone histological transformation (Lee et al, 2017;Selenica et al, 2022;Zhong et al, 2021). While APOBEC activity does not accelerate acquired therapy resistance, A3B expression alters the evolutionary path that PC9 cells take to become gefitinib-resistant.…”

Section: Discussionsupporting

confidence: 79%

“…Interestingly, the APOBEC mutational signature is elevated in tumors from patients who have undergone treatment with EGFR inhibitors and developed acquired resistance to these inhibitors (Selenica et al, 2022). Among these patients, APOBEC signatures are especially high in tumors that have acquired resistance though histological transformation (Lee et al, 2017;Zhong et al, 2021). However, the mechanistic role of APOBEC enzymes in acquired drug resistance to EGFR inhibitors, or how APOBEC mutagenesis affects transdifferentiation, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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APOBEC3 activity promotes the survival and evolution of drug-tolerant persister cells during acquired resistance to EGFR inhibitors in lung cancer

Garcia

Becerra

McKinney

et al. 2023

Preprint

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APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTPs) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises through de novo acquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor deltaNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of deltaNp63 in gefitinib- resistant cells reduces the expression of the p63 target genes IL1alpha/beta and sensitizes these cells to the third- generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs, and suggest that approaches to target deltaNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

APOBEC3 activity promotes the survival and evolution of drug-tolerant persister cells during acquired resistance to EGFR inhibitors in lung cancer

Garcia

Becerra

McKinney

et al. 2023

Preprint

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“…DDP is a first-line chemotherapy drug for lung cancer, but it has side effects and the treatment efficacy varies depending on the conditions of lung cancer patients. 21 , 22 Therefore, there is an urgent need to develop combination therapy to improve the efficacy and reduce the toxicity of DDP. In this study, we investigated the synergistic effects of LBT and DDP on lung cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Lobetyolin suppressed lung cancer in a mouse model by inhibiting epithelial-mesenchymal transition

Liu

et al. 2022

Eur J Histochem

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Traditional Chinese medicines are gaining more attention as promising adjuvant agents for conventional chemotherapy. Recent studies have shown that lobetyolin (LBT) is one of the main bioactive compounds of traditional Chinese medicines and it exhibits anticancer activity in several types of cancer. Therefore, this study aimed to investigate the mechanism by which LBT inhibits lung cancer. A549 human lung cancer cells were treated with LBT. In addition, A549 cells were injected into Balc/b nude mice to establish model of lung cancer. The mice were treated with cisplatin (DDP) or LBT alone or in combination, and tumor growth was monitored. Protein levels of E-cadherin, vimentin and matrix metalloproteinase 9 (MMP9) were detected. We found that the combination of LBT and DDP showed stronger effect to inhibit the proliferation of A549 cells compared to LBT or DDP treatment alone. Wound healing assay showed that the ratio of wound healing was significantly lower in LBT group and DDP group and was the lowest in LBT+DDP group. Transwell invasion assay showed that the invasion ability of A549 cells was the weakest in LBT+DDP group. Protein levels of E-cadherin were the highest while those of vimentin and MMP9 were the lowest in A549 cells treated with LBT+DDP. Nude mouse xenograft tumor model showed that the combination of LBT with DDP had the highest efficacy to inhibit the growth of lung cancer, and tumor tissues of mice treated with LBT+DDP had the lowest expression of vimentin and MMP9 and the highest expression of E-cadherin. In conclusion, LBT significantly enhances the efficacy of chemotherapy on lung cancer, and the mechanism may be related to the inhibition of epithelial-mesenchymal transition.

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“…Jie Huang 1 Shi-Ling Zhang 2 Chao Zhang 1 Weiye Huang 3 Zhenhua Zhang 4 Yu-Qing Chen 1 Jun-Wei Su 1 Hong-Hong Yan 1 Hua-Jun Chen 1 Jin-Ji Yang 1 Junjian Wang 4,5 Yi-Long Wu…”

Section: A U T H O R C O N T R I B U T I O N Smentioning

confidence: 99%

“…2-4 However, this patient population is generally treated as a homogeneous entity, yet their posttransformation prognosis is often worse than that of de novo SCLC. 4,5 Hence, it is rational to define EGFRmutant lung cancer with T-SCLC into distinct subtypes, potentially uncovering new therapeutic targets and vulnerabilities.We conducted a retrospective analysis of 1436 EGFRmutant NSCLC patients at the Guangdong Lung Cancer Institute between January 2017 and December 2021. This cohort included 63 patients who underwent T-SCLC and 97 patients who harboured concomitant RB1 and TP53 alterations along with EGFR mutation (Supporting Information Figure S1).…”

mentioning

confidence: 99%

Genotyping of RB1 status identifies two distinct subtypes in EGFR‐mutant lung cancers with SCLC transformation

Huang,

Zhang,

Zhang

et al. 2024

Clinical & Translational Med

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Dear Editor, In this study, we investigate the significant yet underexplored clinical and molecular heterogeneity in epidermal growth factor receptor (EGFR)-mutant lung cancers transformed into small cell lung cancer (SCLC). Our work addresses a crucial unmet need in understanding the molecular underpinnings of this transformation and introduces a novel predictive model for assessing the transformation hazards in high-risk patients.Up to 14% of EGFR-mutant non-SCLC (NSCLC) patients experience SCLC transformation (T-SCLC) under the selective pressure of EGFR tyrosine kinase inhibitors (TKIs), 1 and the significant heterogeneity within this population is increasingly recognised, including response to EGFR-TKIs, time to transformation, survival and genetic profile. 2-4 However, this patient population is generally treated as a homogeneous entity, yet their posttransformation prognosis is often worse than that of de novo SCLC. 4,5 Hence, it is rational to define EGFRmutant lung cancer with T-SCLC into distinct subtypes, potentially uncovering new therapeutic targets and vulnerabilities.We conducted a retrospective analysis of 1436 EGFRmutant NSCLC patients at the Guangdong Lung Cancer Institute between January 2017 and December 2021. This cohort included 63 patients who underwent T-SCLC and 97 patients who harboured concomitant RB1 and TP53 alterations along with EGFR mutation (Supporting Information Figure S1). Furthermore, T-SCLC patients were stratified into two subgroups based on pre-transformation RB1 status: the EGFR-mutant/RB1-wild subgroup (n = 21) and the EGFR/RB1-mutant subgroup (n = 34). Additionally, EGFR/RB1/TP53-mutant patients were categorised into the transformed subgroup (n = 34) and the untransformed subgroup (n = 27). Notably, the transformed subgroup completely overlapped with the EGFR/RB1-mutant subgroup, as all the patients in the EGFR/RB1-mutant subgroup harboured TP53 mutations simultaneously (Supporting Information: Methods).

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Evolution and genotypic characteristics of small cell lung cancer transformation in non-small cell lung carcinomas

Cited by 4 publications

References 42 publications

APOBEC3 activity promotes the survival and evolution of drug-tolerant persister cells during acquired resistance to EGFR inhibitors in lung cancer

APOBEC3 activity promotes the survival and evolution of drug-tolerant persister cells during acquired resistance to EGFR inhibitors in lung cancer

Lobetyolin suppressed lung cancer in a mouse model by inhibiting epithelial-mesenchymal transition

Genotyping of RB1 status identifies two distinct subtypes in EGFR‐mutant lung cancers with SCLC transformation

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