Small cell lung cancer transformation: From pathogenesis to treatment

Yin, Xiaomeng; Li, Yueyi; Wang, Hang; Jia, Tingting; Wang, Enli; Luo, Yuling; Wei, Yuhao; Qin, Zeyi; Ma, Xuelei

doi:10.1016/j.semcancer.2022.03.006

Cited by 61 publications

(31 citation statements)

References 91 publications

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“…Lung cancer represents the major reason for cancer-related deaths, histologically categorized into two main subtypes: small-cell lung carcinoma (SCLC; 15%) [1] and non-smallcell lung carcinoma (NSCLC; 85%) [2,3]. Lung adenocarcinoma (LUAD) remains the dominating subtype of NSCLC among smokers [4].…”

Section: Introductionmentioning

confidence: 99%

Homeobox A1 Facilitates Immune Escape and Alleviates Oxidative Stress in Lung Adenocarcinoma

Zhao

Tian

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. Recent studies have demonstrated that homeobox A1 (HOXA1) is upregulated in lung cancer due to RNA modifications (N6-methyladenosine), but the specific function of HOXA1 in lung adenocarcinoma (LUAD) remains indistinct. Herein, we investigated the role of HOXA1 in LUAD biology. Methods. This study presented pancancer analysis of associations of HOXA1 with prognosis, TMB, and immune checkpoints. The expression of HOXA1 was detected in LUAD and normal tissues with immunohistochemistry and western blot. Through least absolute shrinkage and selection operator (LASSO) analysis, HOXA1-derived gene model was conducted in LUAD. Correlations of HOXA1 with immune cell infiltrations, immune checkpoints, HLAs, and chemotherapeutic sensitivity were evaluated. Colony formation, proliferation, and migration of LUAD cells with si-HOXA1 transfection were investigated, and the effects of HOXA1 on T cell exhaustion were assessed in vitro. Results. HOXA1 expression was a risk factor of overall survival, disease-specific survival, and progression-free interval of LUAD. HOXA1 exhibited prominent associations with immune cell infiltration, immune checkpoints, and HLAs. HOXA1-derived gene signature reliably and independently predicted LUAD outcomes. Also, high-risk cases presented increased sensitivity to cisplatin, paclitaxel, docetaxel, vinorelbine, and etoposide. HOXA1 knockdown exhibited an inhibitory effect on proliferation and migration abilities of LUAD cells. Silencing HOXA1 weakened the expression of antioxidative stress markers Nrf2/HO-1 and T cell exhaustion marker CD155 in LUAD cells. Moreover, LUAD cells with HOXA1 knockdown enhanced the CD8+ T cell response. Conclusion. Our data support the oncogenic function and prognostic significance of HOXA1 that facilitates immune escape and alleviates oxidative stress of LUAD.

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Section: Introductionmentioning

confidence: 99%

Homeobox A1 Facilitates Immune Escape and Alleviates Oxidative Stress in Lung Adenocarcinoma

Zhao

Tian

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…These patients typically have a high risk for small cell transformation (18%) [ 21 ]. Aside from RB1 and TP53 losses, the SOX family mutation, PI3K/AKT pathway, MYC and AURKA amplification, as well as Notch signaling downregulation, may underlie mechanisms of transformation [ 22 ]. In regard to squamous cell transformation, Schoenfeld et al characterized the mechanisms of resistance to osimertinib.…”

Section: Discussionmentioning

confidence: 99%

Histological Transformation after Acquired Resistance to the Third-Generation EGFR-TKI in Patients with Advanced EGFR-Mutant Lung Adenocarcinoma

Lee

Huang

et al. 2022

Medicina

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Background and Objectives: Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is one of the standard-of-care therapies in patients with EGFR-mutant lung adenocarcinoma; however, acquired resistance inevitably developed. Despite the proposition of histological transformation being one of the resistance mechanisms, its incidence and influence on outcome remain unclear. Materials and Methods: This was a retrospective study conducted at Taichung Veterans General Hospital on patients with advanced EGFR-mutant lung adenocarcinoma receiving the third-generation EGFR-TKI. Only patients receiving rebiopsy were included in the analysis. Results: A total of 55 patients were studied. Eight patients (14.5%) showed histological transformation, including three small cell carcinoma, three squamous cell carcinoma, one large cell neuroendocrine carcinoma, and one with a mixture of adenocarcinoma and squamous cell carcinoma components. The median treatment duration of the third-generation EGFR-TKI before rebiopsy was numerically longer in patients with histological transformation than those without (16.0 vs. 10.9 months). Both the overall survival time from the start of third-generation EGFR-TKI initiation (30.8 vs. 41.2 months) and from rebiopsy (6.6 vs. 12.9 months) to mortality were numerically shorter amongst the transformed population. All patients in the transformed group did not respond to the next line of systemic treatment. One patient with histological transformation receiving local treatment for the metastatic site had a longer overall survival. Conclusions: Repeating biopsy to identify histological transformation should be considered in patients with progression to the third-generation EGFR-TKI. Histological transformations could contribute to the acquired resistance with the implication of a worse prognosis. Further studies are needed to determine the optimal therapy for these patients.

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“…Additional genomic alterations, including those that activate the PI3K/AKT family and downregulate NOTCH signaling and those affecting the MYC and SOX families, AKT pathway activation and other molecules, also participate in the transformation from EGFR-mutant NSCLC. However, the precise mechanisms in other cases are unclear [ 84 ]. In addition, squamous cell transformation was recently identified as a mechanism of acquired EGFR-TKI resistance that occurs in approximately 15% of patients who received osimertinib as both first- and second-line therapy.…”

Section: Egfr-dependent Drug Resistance Mechanismsmentioning

confidence: 99%

Emerging strategies to overcome resistance to third-generation EGFR inhibitors

et al. 2022

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Epidermal growth factor receptor (EGFR), the receptor for members of the epidermal growth factor family, regulates cell proliferation and signal transduction; moreover, EGFR is related to the inhibition of tumor cell proliferation, angiogenesis, invasion, metastasis, and apoptosis. Therefore, EGFR has become an important target for the treatment of cancer, including non-small cell lung cancer, head and neck cancer, breast cancer, glioma, cervical cancer, and bladder cancer. First- to third-generation EGFR inhibitors have shown considerable efficacy and have significantly improved disease prognosis. However, most patients develop drug resistance after treatment. The challenge of overcoming intrinsic and acquired resistance in primary and recurrent cancer mediated by EGFR mutations is thus driving the search for alternative strategies in the design of new therapeutic agents. In view of resistance to third-generation inhibitors, understanding the intricate mechanisms of resistance will offer insight for the development of more advanced targeted therapies. In this review, we discuss the molecular mechanisms of resistance to third-generation EGFR inhibitors and review recent strategies for overcoming resistance, new challenges, and future development directions.

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Small cell lung cancer transformation: From pathogenesis to treatment

Cited by 61 publications

References 91 publications

Homeobox A1 Facilitates Immune Escape and Alleviates Oxidative Stress in Lung Adenocarcinoma

Homeobox A1 Facilitates Immune Escape and Alleviates Oxidative Stress in Lung Adenocarcinoma

Histological Transformation after Acquired Resistance to the Third-Generation EGFR-TKI in Patients with Advanced EGFR-Mutant Lung Adenocarcinoma

Emerging strategies to overcome resistance to third-generation EGFR inhibitors

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