Differential expression of the MYC-Notch axis drives divergent responses to the front-line therapy in central and peripheral extensive-stage small-cell lung cancer

Abstract

Central and peripheral extensive-stage small-cell lung cancer (ES-SCLC) are reported to be two distinct tumor entities, but their responses to the front-line therapies and underlying biological mechanisms remain elusive. In this study, we first compared the outcomes of central and peripheral ES-SCLC receiving front-line chemotherapy or chemo-immunotherapy with a cohort of 265 patients. Then we performed single-cell RNA sequencing (scRNA-seq) on nine treatment-naïve ES-SCLC samples to investigate potential mechanisms underlying the response differences. Under chemotherapy, the peripheral type had a lower objective response rate (44.8% vs. 71.2%, p = 0.008) and shorter progression-free survival (median 3.4 vs. 5.1 months, p = 0.001) than the central type. When comparing chemo-immunotherapy with chemotherapy, the peripheral type showed a greater potential to reduce progression (HR, 0.18 and 0.52, respectively) and death (HR, 0.44 and 0.91 respectively) risks than the central type. Concerning the scRNA-seq data, the peripheral type was associated with chemo-resistant and immune-responsive tumoral and microenvironmental features, including a higher expression level of MYC-Notch-non-neuroendocrine (MYC-Notch-non-NE) axis and a more potent antigen presentation and immune activation status. Our results revealed that central and peripheral ES-SCLC had distinct responses to front-line treatments, potentially due to differential activation statuses of the MYC-Notch-non-NE axis.

Keywords

chemo-immunotherapy / extensive-stage small-cell lung cancer / primary tumor location / single-cell RNA sequencing

References

[1] Zugazagoitia J, Paz-Ares L. Extensive-stage small-cell lung cancer: first-line and second-line treatment options. J Clin Oncol. 2022; 40(6): 671-680.

[2] Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021; 7(1): 3.

[3] Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006; 24(28): 4539-4544.

[4] Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018; 379(23): 2220-2229.

[5] Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label. Lancet. 2019; 394(10212): 1929-1939.

[6] Cheng Y, Han L, Wu L, et al. Effect of first-line serplulimab vs placebo added to chemotherapy on survival in patients with extensive-stage small cell lung cancer: the ASTRUM-005 randomized clinical trial. JAMA. 2022; 328(12): 1223-1232.

[7] Wang J, Zhou C, Yao W, et al. Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022; 23(6): 739-747.

[8] Yang S, Zhang Z, Wang Q. Emerging therapies for small cell lung cancer. J Hematol Oncol. 2019; 12(1): 47.

[9] Wang S, Zimmermann S, Parikh K, Mansfield AS, Adjei AA. Current diagnosis and management of small-cell lung cancer. Mayo Clin Proc. 2019; 94(8): 1599-1622.

[10] Schultheis AM, Scheel AH, Ozretić L, et al. PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer. 2015; 51(3): 421-426.

[11] Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021; 39(6): 619-630.

[12] Pujol J-L, Greillier L, Audigier-Valette C, et al. A randomized non-comparative phase II study of anti-programmed cell death-ligand 1 atezolizumab or chemotherapy as second-line therapy in patients with small cell lung cancer: results from the IFCT-1603 trial. J Thorac Oncol. 2019; 14(5): 903-913.

[13] Goldman JW, Garassino MC, Chen Y, et al. LBA86 Durvalumab (D) ± tremelimumab (T) + platinum-etoposide (EP) in 1L ES-SCLC: characterization of long-term clinical benefit and tumour mutational burden (TMB) in CASPIAN. Ann Oncol. 2020; 31(suppl_4): S1212-S3.

[14] Paz-Ares L, Goldman JW, Garassino MC, et al. PD-L1 expression, patterns of progression and patient-reported outcomes (PROs) with durvalumab plus platinum-etoposide in ES-SCLC: results from CASPIAN. Ann Oncol. 2019; 30(suppl_5): v928-v9..

[15] Longo V, Catino A, Montrone M, et al. What are the biomarkers for immunotherapy in SCLC?. Int J Mol Sci. 2021; 22(20): 11123.

[16] Bandoh S, Fujita J, Ueda Y, et al. Expression of carcinoembryonic antigen in peripheral-or central-located small cell lung cancer: its clinical significance. Jpn J Clin Oncol. 2001; 31(7): 305-310.

[17] Sakurai H, Asamura H, S-i Watanabe, Suzuki K, Tsuchiya R. Clinicopathologic features of peripheral squamous cell carcinoma of the lung. Ann Thorac Surg. 2004; 78(1): 222-227.

[18] Kanaji N, Sakai K, Ueda Y, et al. Peripheral-type small cell lung cancer is associated with better survival and higher frequency of interstitial lung disease. Lung Cancer. 2017; 108: 126-133.

[19] Gao Y, Dong Y, Zhou Y, Chen G, Hong X, Zhang Q. Peripheral tumor location predicts a favorable prognosis in patients with resected small cell lung cancer. Int J Clin Pract. 2022; 2022: 4183326.

[20] Yu S, Jia M, Li Y, Sun P-L, Gao H, Differential expression of PD-L1 in central and peripheral and TTF1-positive and -negative small-cell lung cancer. Front Med (Lausanne). 2020; 7: 621838.

[21] Wang L, Wang J, Hu J, et al. Distinct patterns of somatic genomic alterations and mutational signatures in central and peripheral-type small-cell lung cancer. Transl Lung Cancer Res. 2021; 10(4): 1747-1760.

[22] Miyauchi E, Motoi N, Ono H, et al. Distinct characteristics of small cell lung cancer correlate with central or peripheral origin: subtyping based on location and expression of transcription factor TTF-1. Medicine (Baltimore). 2015; 94(51): e2324.

[23] Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019; 19(5): 289-297.

[24] Frese KK, Simpson KL, Dive C. Small cell lung cancer enters the era of precision medicine. Cancer Cell. 2021; 39(3): 297-299.

[25] Owonikoko TK, Dwivedi B, Chen Z, et al. YAP1 expression in sclc defines a distinct subtype with t-cell-inflamed phenotype. J Thorac Oncol. 2021; 16(3): 464-476.

[26] Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021; 39(3): 346-360.e7.

[27] Li Y, Jin J, Bai F. Cancer biology deciphered by single-cell transcriptomic sequencing. Protein Cell. 2022; 13(3): 167-179.

[28] Xiangyu P, Na F, Chen X. Deciphering transcriptional bursts and enhancer dynamics: advancing cancer therapeutics through single-cell global run-on sequencing. MedComm Oncol. 2024; 3.

[29] Wu F, Fan J, He Y, et al. Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nat Commun. 2021; 12(1): 2540.

[30] Leader AM, Grout JA, Maier BB, et al. Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification. Cancer Cell. 2021; 39(12): 1594-1609.e12.

[31] Wang C, Yu Q, Song T, et al. The heterogeneous immune landscape between lung adenocarcinoma and squamous carcinoma revealed by single-cell RNA sequencing. Signal Transduct Target Ther. 2022; 7(1): 289.

[32] Guo X, Zhang Y, Zheng L, et al. Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat Med. 2018; 24(7): 978-985.

[33] Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020; 17(8): 807-821.

[34] Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022; 12(1): 31-46.

[35] Tian Y, Li Q, Yang Z, et al. Single-cell transcriptomic profiling reveals the tumor heterogeneity of small-cell lung cancer. Signal Transduct Target Ther. 2022; 7(1): 346.

[36] Cheng C, Zhu G, Li Y, et al. Single-cell transcriptome analysis reveals cellular and molecular alterations in small cell lung cancer tumors following chemotherapy. Int J Cancer. 2023; 153(6): 1273-1286.

[37] Chan JM, Quintanal-Villalonga Á, Gao VR, et al. Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer. Cancer Cell. 2021; 39(11): 1479-1496.

[38] Stewart CA, Gay CM, Xi Y, et al. Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer. Nat Cancer. 2020; 1: 423-436.

[39] Herzog BH, Devarakonda S, Govindan R. Overcoming chemotherapy resistance in SCLC. J Thorac Oncol. 2021; 16(12): 2002-2015.

[40] Ireland AS, Micinski AM, Kastner DW, et al. MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate. Cancer Cell. 2020; 38(1).

[41] Chen J, Guanizo AC, Jakasekara WSN, et al. MYC drives platinum resistant SCLC that is overcome by the dual PI3K-HDAC inhibitor fimepinostat. J Exp Clin Cancer Res. 2023; 42(1): 100.

[42] Scattolin D, Maso AD, Ferro A, et al. The emerging role of Schlafen-11 (SLFN11) in predicting response to anticancer treatments: focus on small cell lung cancer. Cancer Treat Rev. 2024; 128: 102768.

[43] Lim JS, Ibaseta A, Fischer MM, et al. Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature. 2017; 545(7654): 360-364.

[44] Zhang W, Girard L, Zhang Y-A, et al. Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res. 2018; 7(1): 32-49.

[45] Liu L, Bai X, Wang J, et al. Combination of TMB and CNA stratifies prognostic and predictive responses to immunotherapy across metastatic cancer. Clin Cancer Res. 2019; 25(24): 7413-7423.

[46] Li B-H, Garstka MA, Li Z-F. Chemokines and their receptors promoting the recruitment of myeloid-derived suppressor cells into the tumor. Mol Immunol. 2020; 117: 201-215.

[47] Kim YS, Nabet B, Chen H, et al. MA17.11 NOTCH1 expression is associated with overall survival in small cell lung cancer patients treated with atezolizumab in IMpower133. J Thorac Oncol. 2024; 19(10): S127.

[48] Owen DH, Giffin MJ, Bailis JM, Smit M-AD, Carbone DP, He K. DLL3: an emerging target in small cell lung cancer. J Hematol Oncol. 2019; 12(1): 61.

[49] Shirasawa M, Yoshida T, Shiraishi K, et al. Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer. Br J Cancer. 2023; 129(12): 2003-2013.

[50] Watanabe J, Muro K, Shitara K, et al. Panitumumab vs bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, left-sided metastatic colorectal cancer: a randomized clinical trial. JAMA. 2023; 329(15): 1271-1282.

[51] Xie X, Li X, Tang W, Xie P, Tan X. Primary tumor location in lung cancer: the evaluation and administration. Chin Med J (Engl). 2021; 135(2): 127-136.

[52] Zhou F, Hou L, Ding T, et al. Distinct clinicopathologic features, genomic characteristics and survival of central and peripheral pulmonary large cell neuroendocrine carcinoma: from different origin cells?. Lung Cancer. 2018; 116: 30-37.

[53] Sutherland KD, Proost N, Brouns I, Adriaensen D, Song J-Y, Berns A. Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer Cell. 2011; 19(6): 754-764.

[54] Jett JR, Schild SE, Kesler KA, Kalemkerian GP, Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013; 143(suppl_5): e400S-e19S.

[55] Hao Y, Hao S, Andersen-Nissen E, et al. Integrated analysis of multimodal single-cell data. Cell. 2021; 184(13): 3573-3587.e29.

[56] Wu T, Hu E, Xu S, et al. clusterProfiler 40: A universal enrichment tool for interpreting omics data Innovation (Camb). 2021; 2(3): 100141.

[57] Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015; 43(7): e47.

[58] Tirosh I, Izar B, Prakadan SM, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016; 352(6282): 189-196.

[59] Jin S, Guerrero-Juarez CF, Zhang L, et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021; 12(1): 1088.

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