bims-necame 2026-04-12 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2026–04–12
eight papers selected by
Grigor Varuzhanyan, UCLA

TRIM36 and CAMK2N2 regulate ferroptosis and antigen presentation in small cell lung cancer.
Folate Receptor α Contributes to Radiation Resistance in Neuroendocrine Prostate Cancer by Regulating Redox Homeostasis.
BMX inhibition overcomes small cell lung cancer chemoresistance by stabilizing E2F1 via ERK1/2-Cyclin D1/CDK4/6 axis.
POU2F3 in SCLC: Diagnostic Utility in Neuroendocrine Low/Negative SCLC and Discrimination From Other Thoracic Malignancies and Other Small Blue Round Cell Tumors.
Targeting KIFC1 to disrupt centrosome clustering and trigger anaphase catastrophe in small-cell lung cancer.
Proof-of-concept study of clinical use of blood-based MAVS biosensor in predicting immunotherapy response in SCLC patients.
Evidence for the transformation of a subset of pulmonary carcinoids to small cell lung carcinomas through shared molecular alterations.
Retinoblastoma Proficient Small Cell Carcinoma: A Novel Entity with Therapeutic Vulnerability?

iScience. 2026 Apr 17. 29(4): 115310

TRIM36 and CAMK2N2 regulate ferroptosis and antigen presentation in small cell lung cancer.

Yifan Cai, Shuang Zhu, Honglin Wang, Fang Huang, Zhongyuan Yin, Jun Nie.

  Small cell lung cancer (SCLC) is a highly aggressive tumor with poor prognosis. Ferroptosis is closely linked to tumor antigen presentation: it affects antigen presentation efficiency via immunostimulatory signals, while CD8+ T cell activation induced by antigen presentation promotes tumor cell ferroptosis by secreting IFNγ. This study used multi-omics analyses and machine learning to screen key genes, verified by in vitro/in vivo experiments. TRIM36 and CAMK2N2 were significantly upregulated in SCLC, negatively correlating with patient survival, effector memory CD8+ T cell infiltration, and tumor MHC I expression. They suppress SCLC antigen presentation via ferroptosis-dependent/independent mechanisms, limiting T cell function. TRIM36 and CAMK2N2 are promising SCLC biomarkers and therapeutic targets, providing clues to unravel ferroptosis-antigen presentation associations in tumor cells and optimize immunotherapeutic strategies.

Keywords:  Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2026.115310
bioRxiv. 2026 Mar 30. pii: 2026.03.26.714502. [Epub ahead of print]

Folate Receptor α Contributes to Radiation Resistance in Neuroendocrine Prostate Cancer by Regulating Redox Homeostasis.

Hira Lal Goel, Tao Wang, Boris S Dimitrov, Ayush Kumar, Christi A Silva, Thomas J FitzGerald, Arthur M Mercurio.

Ionizing radiation can be an effective therapy for prostate cancer. Unfortunately, however, more aggressive prostate cancers such as neuroendocrine prostate cancer (NEPC) are often radiation resistant, which contributes to their high degree of morbidity and mortality. In this study, we used an unbiased approach to identify novel mechanisms that contribute to resistance to radiation and that are associated with neuroendocrine differentiation. Specifically, we compared the expression of cell surface proteins by mass spectrometry in prostate cancer cell lines that had been either untreated or treated with radiation to induce resistance, a process that also promotes neuroendocrine differentiation. Among the proteins identified by this screen, we focused on folate receptor α (FRα) because of its known biological functions and the fact that it is a validated therapeutic target. Our data reveal that FRα has a causal role in enabling prostate cancer cells to resist radiation. Importantly, we also demonstrate that the expression of FRα is regulated by HIF-1α, which also has a causal role in radiation resistance and neuroendocrine differentiation. Given that the ability of cells to resist damage and death in response to ionizing radiation depends largely on their ability to buffer the substantial increase in reactive oxygen species (ROS) that is generated by radiation, we also demonstrate that the folate-FRα axis promotes radiation resistance by sustaining intracellular glutathione levels that buffer this increase in ROS. In summary, the data reported here highlight a novel role for FRα in resistance to ionizing radiation that is intimately associated with the hypoxic microenvironment of NEPC and the ability of the folate-FRa axis to maintain redox homeostasis.

DOI: https://doi.org/10.64898/2026.03.26.714502
Signal Transduct Target Ther. 2026 Apr 08. pii: 125. [Epub ahead of print]11(1):

BMX inhibition overcomes small cell lung cancer chemoresistance by stabilizing E2F1 via ERK1/2-Cyclin D1/CDK4/6 axis.

Ting Wu, Shuang Qi, Chenliang Shi, Chao Wu, Qingwang Liu, Chen Hu, Jie Hu, Aoli Wang, Jing Liu, Ziping Qi, Wenchao Wang, Qingsong Liu.

Chemotherapy resistance remains a critical bottleneck limiting its clinical efficacy in small cell lung cancer (SCLC), with its core mechanisms and targeted intervention strategies urgently requiring breakthroughs. Our study revealed that the BMX (bone marrow tyrosine kinase on chromosome X)-E2F1 (E2F transcription factor 1) axis is a pivotal regulator of chemoresistance in SCLC. Synchronous upregulation of phosphorylated BMX (Tyr566) and E2F1 was observed in SCLC tissues and cells. Mechanistically, BMX stabilized E2F1 via the ERK1/2 (extracellular signal-regulated kinase 1/2)-Cyclin D1/CDK4/6 (cyclin-dependent kinase 4/6) signaling axis, phosphorylating E2F1 at Ser332/337 and inhibiting its degradation via the ubiquitin-proteasome pathway. Inhibition or knockdown of BMX reduced E2F1 stability, promoting its degradation and reversing chemoresistance. E2F1 knockdown decreased the expression of genes associated with cell cycle regulation, migration, invasion, and DNA repair, further sensitizing chemoresistant SCLC cells to cisplatin. We also discovered IHMT-15137, a potent and selective BMX inhibitor. In vitro studies using SCLC patient-derived cells (PDCs)/patient-derived organoids (PDOs) and chemoresistant cell lines revealed that IHMT-15137, combined with cisplatin, synergistically induced cell cycle arrest, apoptosis, and DNA damage while suppressing cell migration and invasion. In vivo xenograft models demonstrated that the combination significantly inhibited tumor growth without causing significant toxicity. Our findings reveal the molecular mechanisms of SCLC chemoresistance and suggest potential therapeutic strategies targeting the BMX-E2F1 axis to overcome this challenge.

DOI: https://doi.org/10.1038/s41392-026-02644-1
Lab Invest. 2026 Apr 07. pii: S0023-6837(26)00054-1. [Epub ahead of print] 106124

POU2F3 in SCLC: Diagnostic Utility in Neuroendocrine Low/Negative SCLC and Discrimination From Other Thoracic Malignancies and Other Small Blue Round Cell Tumors.

Xiaoyan Chen, Fangfang Zou, Haimin Xu, Zhihan Zhang, Jing Wang, Yue Li, Jingdan Jia, Shanshan Sun, Chaofu Wang, Jing Zhang.

   INTRODUCTION: POU2F3 is a newly identified immunohistochemical marker specific for the chemosensory tuft cells-related subtype of small cell lung carcinoma (SCLC-P). The characteristics of SCLC-P remain incompletely defined, and POU2F3 expression patterns across different organs and tissue types are poorly documented.
MATERIALS AND METHODS: We assessed POU2F3 expression in 253 SCLC, with comprehensive clinicopathologic and genomic characterization of POU2F3-positive tumors. POU2F3 expression profiles were investigated in other major lung cancer types (n = 2497) and other tumors across different organs and tissue types (n = 196).
RESULTS: POU2F3 was expressed in 10.28% (26/253) of all SCLC and was strongly associated with low expression of standard neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1). In NE-low/negative SCLC and NE-high SCLC, the POU2F3 positive rates were 83.33% (20/24) and 2.62% (6/229), respectively. Additionally, POU2F3 was detected in SCC (2.35%) and LCNEC (25%), but was negative in lung adenocarcinoma, NUT carcinoma, LCC, PC, SMARCA4-UT, AC, and ACC. Notably, the highly heterogeneity of POU2F3 expression were observed in 7.3% (3/41) surgical SCLC specimens. In extrapulmonary tumors, POU2F3 was positive in 37.5% (6/16) of extra-SCNECs, 16.67% (5/30) of thymic tumors, 1 of 2 extra-LCNECs, and 1 of 1 NPC. SCLC-P tends to be more prevalent in surgical specimens (P=0.009) and earlier TNM stage (P=0.045). Next-generation sequencing revealed that SCLC-P (n=6) exhibited enrichment in MYC gene amplification and lower mutation rate of RB1, but similar rates of TP53 and PTEN alterations as POU2F3-negative SCLC (n = 13).
CONCLUSIONS: This study establishes POU2F3 as a critical diagnostic biomarker for neuroendocrine-low/negative SCLC, demonstrating high specificity in distinguishing SCLC-P from other thoracic malignancies and small blue round cell tumors. We delineate the distinct clinicopathological-genomic profile of POU2F3-driven SCLC (SCLC-P), providing a foundation for its diagnostic application. Further validation in expanded cohorts is warranted to confirm its clinical utility.

Keywords:  Clinical and genomic characteristics; NE low/negative SCLC; POU2F3; SCLC-P

DOI:  https://doi.org/10.1016/j.labinv.2026.106124
JCI Insight. 2026 Apr 08. pii: e199352. [Epub ahead of print]11(7):

Targeting KIFC1 to disrupt centrosome clustering and trigger anaphase catastrophe in small-cell lung cancer.

Natsuki Nakagawa, Minemichi Toda, Akiko Kunita, Masafumi Horie, Masakatsu Tokunaga, Hiroaki Ikushima, Mirei Ka, Takahiro Iida, Manabu Shigeoka, Yukinobu Ito, Takahiro Ando, Kousuke Watanabe, Yasunori Ota, Xi Liu, Ethan Dmitrovsky, Hidenori Kage, Masanori Kawakami.

  Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.

Keywords:  Cell biology; Lung cancer; Oncology

DOI:  https://doi.org/10.1172/jci.insight.199352
Transl Oncol. 2026 Apr 04. pii: S1936-5233(26)00093-8. [Epub ahead of print]67 102756

Proof-of-concept study of clinical use of blood-based MAVS biosensor in predicting immunotherapy response in SCLC patients.

Luisa Amato, Ines Tavoletta, Caterina De Rosa, Mimimorena Seggio, Francesco Arcadio, Sara Capaldo, Faiz Ul Haq, Concetta Tuccillo, Carla Esposito, Gaetano di Guida, Francesca Iommelli, Viviana De Rosa, Alfonso Reginelli, Salvatore Cappabianca, Floriana Morgillo, Fortunato Ciardiello, Valerio Nardone, Nunzio Cennamo, Carminia Maria Della Corte, Luigi Zeni.

  Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with poor prognosis and limited benefit from immune checkpoint inhibitors (ICIs). Biomarker-driven patient stratification has been hindered by small biopsy samples, high tumor heterogeneity, and the limited predictive value of PD-L1 and tumor mutation burden. Mitochondrial antiviral-signaling protein (MAVS) has emerged as a potential immune activation marker, particularly in patients receiving DNA-damaging therapies. We report a proof-of-concept clinical study evaluating a surface plasmon resonance-plastic optical fiber (SPR‑POF) biosensor functionalized with anti-MAVS antibodies to detect the protein in serum from SCLC patients undergoing chemo-immunotherapy, with or without radiotherapy. The biosensor achieved a limit of detection of 0.13 nM in human diluted serum and demonstrated high selectivity against common serum proteins. In a cohort stratified as best responders (disease control >6 months) and non-responders (progressive disease as best response), MAVS levels measured in responders were on average tenfold higher than in non-responders, consistent with previous preclinical PBMC and western blot data. The SPR‑POF platform demonstrated portability, cost-effectiveness (estimated 5 USD/unit), and operational simplicity, highlighting its potential for point-of-care testing (POCT) applications. Although limited by small patient numbers, these findings support MAVS as a promising predictive biomarker in SCLC, warranting validation in larger prospective studies.

Keywords:  Blood-based biomarker; Immune sensing; Liquid biopsy; MAVS; SCLC

DOI:  https://doi.org/10.1016/j.tranon.2026.102756
Front Oncol. 2026 ;16 1768871

Evidence for the transformation of a subset of pulmonary carcinoids to small cell lung carcinomas through shared molecular alterations.

Ruirui Fan, Jie Gao.

   Background: Pulmonary carcinoid and small cell lung carcinomas represent fundamentally distinct tumors in terms of molecular pathogenesis, pathological features, treatment, and prognosis. Whether any pathogenic link exists between pulmonary carcinoids and small cell carcinomas remains poorly understood. Elucidating the potential for carcinoids to undergo transformation into small cell lung carcinomas is critical for early intervention, treatment personalization, and prognostic assessment.
Methods: H&E staining was performed to assess histomorphological transitions between pulmonary atypical carcinoids and small cell lung carcinomas. Immunohistochemistry was subsequently applied to compare the immunophenotypic profiles of two tumors. Molecular profiling was conducted to evaluate clonal relatedness and the presence of progressive genetic alterations, thereby providing evidence for transformation.
Results: In addition to the atypical carcinoid and small cell lung carcinomas morphological characteristics, the lesion areas also present hybrid morphological characteristics of both tumors. Immunohistochemical analysis demonstrated distinct profiles between the two tumors: atypical carcinoids exhibited a low Ki67 proliferative index, high TP53 expression, and loss of RB1 expression, whereas small cell lung carcinomas showed a high Ki67 proliferative index, low TP53 expression, and loss of RB1 expression. Furthermore, clonal evolution analysis revealed that the two tumor components shared a set of 160 identical somatic mutations (accounting for approximately 16% of the total mutations in each component).
Conclusion: This study delineates a dynamic evolutionary process within the pulmonary neuroendocrine tumor spectrum, confirming that a subset of atypical carcinoids can progress to small cell lung carcinoma through a transformation pathway.

Keywords:  genetic analysis; neuroendocrine tumor; pathological analysis; pulmonary carcinoid; small cell lung carcinoma; tumor transformation

DOI:  https://doi.org/10.3389/fonc.2026.1768871
J Thorac Oncol. 2026 Apr 02. pii: S1556-0864(26)00167-X. [Epub ahead of print] 103714

Retinoblastoma Proficient Small Cell Carcinoma: A Novel Entity with Therapeutic Vulnerability?

Afshin Dowlati, Reza Ferdousi, Abhishek Ajay, Cammie Brewster, Brandon J Grubb, Angelina Golya, Omid Savari, Minh Lam, Gary M Wildey.

  Small-cell lung cancer (SCLC), frequently characterized by early metastasis and rapid development of therapy resistance, remains the most aggressive form of lung cancer. Recent transcriptional profiling has redefined SCLC as a heterogeneous spectrum of biologically distinct subtypes with potential differential therapeutic vulnerabilities, fostering optimism that molecular stratification may improve clinical outcomes. Within this framework, growing interest has focused on the rare subset of SCLC that retains functional retinoblastoma (Rb) protein. While recognizing Rb-proficient SCLC as a distinct entity continues to evolve, transcriptomic correlations suggest possible links with YAP1 and non-neuroendocrine expression programs. Preclinical studies further indicate that Rb protein retention may confer unique therapeutic sensitivity, particularly to CDK4/6 inhibition, which not only suppresses tumor proliferation but also potentially reshapes the immune microenvironment to enhance immunotherapy responses. More importantly, RB1 functional status may also modulate sensitivity to additional therapeutic modalities, highlighting its broader relevance to the evolving SCLC treatment landscape. Integrating molecularly informed strategies accounting for RB1 proficiency and its transcriptional landscape will be pivotal to overcoming the long-standing therapeutic impasse in SCLC, offering a roadmap for the development of effective, precision-guided therapies.

Keywords:  CDK4/6 inhibitors; Chemo-refractory; Chemo-sensitive; Loss-of-function (LOF); RB1; Small-cell lung cancer (SCLC); Targeted sequencing; Whole exome sequencing (WES); Whole genome sequencing (WGS)

DOI:  https://doi.org/10.1016/j.jtho.2026.103714