bims-necame 2026-05-03 papers

Issue of 2026–05–03
four papers selected by
Grigor Varuzhanyan, UCLA

Mol Cancer Ther. 2026 May 01.

HDAC inhibition unlocks tumor plasticity and enhances immunotherapy response in Myc-driven small cell lung cancer.

Azam Ghafoor, Linying Zhu, Zoe Weaver Ohler, Rajaa El Meskini, Haoxuan Ying, Devon Atkinson, Amanda Day, Nathan Pate, Laura Bassel, Weixin Wang, Katherine R Calvo, Lorinc Pongor, Kanak Parmar, Yves Pommier, Anish Thomas, Yilun Sun.

Small Cell Lung Cancer (SCLC) is a highly aggressive malignancy, accounting for approximately 15% of all lung cancer cases. Characterized by low immunogenicity, SCLC may utilize epigenetic mechanisms to evade immune detection. Here, we demonstrate that entinostat, a class I histone deacetylase inhibitor (HDACi), upregulates immune-related genes in human SCLC cells. In vivo, we confirmed that entinostat treatment increased the expression of immunecheckpoint ligands and antigen presentation machinery in Myc-driven tumors in a Rb1/Trp53/MycT58A (RPM) SCLC mouse model, while shifting tumors from a neuroendocrine (NE)-high to a NE-low phenotype, and was associated with increased T-cell infiltration Notably, combining entinostat with anti-PD-1 immunotherapy suppresses tumor growth and significantly prolonged survival in RPM allograft models. These findings underscore the potential of entinostat to reprogram the NE status of SCLC, enhance immune checkpoint blockade efficacy, and improve therapeutic outcomes.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1077

Oncogene. 2026 Apr 29.

KDM4B/DHX9 promotes chemoresistance in small-cell lung cancer through the MYCN-driven signaling pathway.

Qiong Lyu, Huiying Liu, Weitao Shen, Zhihong Lin, Yueming Zhang, Haoxuan Ying, Qianshan Long, Xiang Cao, Jian Zhang, Jian Shi, Zhengang Qiu.

Small cell lung cancer (SCLC) is prone to developing chemoresistance, which is associated with epigenetic reprogramming. While LSD1-mediated histone demethylation has been reported, a systematic investigation into the role of histone demethylases in SCLC chemoresistance is lacking. In this study, we established nine chemoresistant cell lines from parental cells via gradual dose escalation and conducted RNA sequencing, followed by linear regression and random effects meta-analysis to identify genes associated with chemoresistance among 23 histone demethylases. We subsequently validated our findings using two neuroendocrine SCLC cell lines and their corresponding chemoresistant counterparts. We identified KDM4B as a key driver of chemoresistance, with immunohistochemical analysis revealing its elevated expression in chemoresistant tissues from SCLC patients, although its association with neuroendocrine subtypes warrants further investigation. KDM4B promoted chemoresistance through the Hedgehog pathway by enhancing cell proliferation and stemness. Mechanistically, KDM4B interacts with DHX9 and corecruits to the MYCN promoter to promote its transcription and activate the Hedgehog signaling pathway. An inhibitor of DHX9 had synergistic antitumor effects with cisplatin and etoposide, and effectively rescued the chemosensitivity of SCLC both in vitro and in vivo. These findings provide valuable insights for future studies aimed at developing therapeutic strategies to overcome chemoresistance in SCLC.

DOI: https://doi.org/10.1038/s41388-026-03798-6

bioRxiv. 2026 Apr 19. pii: 2026.04.15.716394. [Epub ahead of print]

CXCL-CXCR2 signaling drives cancer-endothelium interactions in SCLC metastatic seeding.

Zhang Yang, Andy Xu, Nicholas Hughes, Chien-Wei Peng, Adrienne Visani, Susrutha Puthanmadhom Narayanan, Xue Wen Ng, Isabella Guppy, Chris Roberts, Yaoxuan You, Monte M Winslow, David W Piston, Jon Park, Zhonglin Lyu, Feng Chen, Li Ding, Rui Tang.

Small cell lung cancer (SCLC) is a highly metastatic malignancy with tropism to the liver, yet the signals that enable organ-specific metastatic colonization remain largely undefined. During metastasis, disseminated cancer cells first encounter endothelial cells (ECs) at the vascular-tissue interface, positioning cancer-endothelium crosstalk as a key determinant of metastatic success. Defining the signaling pathways underlying this reciprocal communication may uncover actionable vulnerabilities for preventing and treating this lethal disease. Here, we uncover an EC-derived CXCL chemokine program that activates cancer-intrinsic CXCR2-RAC1 signaling as a critical mediator of SCLC liver metastasis. By integrating in vitro and in vivo models, we show that SCLC cells induce robust CXCL chemokine expression from liver ECs, which in turn enhances SCLC migration and reinforces cancer cell-EC interactions. We applied highly quantitative metastatic colony barcode sequencing coupled with individual gene inactivation to demonstrate that CXCR2 is essential for SCLC migration and liver metastatic seeding. Mechanistically, CXCL-CXCR2 signaling activates RAC1-dependent F-actin assembling to drive SCLC motility during CXCL-induced metastatic seeding. Pharmacologic inhibition of CXCR2 or RAC1 suppresses SCLC migration and prevents SCLC liver metastasis. Together, our research defined a chemokine-driven signaling circuit that governs cancer-endothelium communication during the metastatic cascade and nominate the CXCL-CXCR2-RAC1 axis as a promising therapeutic vulnerability for preventing and treating metastatic SCLC.

DOI: https://doi.org/10.64898/2026.04.15.716394

Cancer Treat Res Commun. 2026 Mar 22. pii: S2468-2942(26)00101-2. [Epub ahead of print]47 101190

The genomic, transcriptomic, and immunologic landscape of TEM8 (ANTXR1) in neuroendocrine neoplasms (NENs) including small-cell lung cancer (SCLC).

Samuel A Kareff, Harris Krause, Andrew Elliott, Timothy Samec, Gilberto Lopes, Peter J Hosein, Chinmay T Jani, Emil Lou, Heloisa Soares, Marco Magistri, Daniel Sumarriva, Matthew Oberley, Aman Chauhan.

PURPOSE: The TEM8 receptor (coded by ANTXR1) plays several roles in oncogenesis and novel oncolytic therapies, such as the SVV-01 virus, uniquely bind this protein in neuroendocrine tumor (NET) histologies, such as small-cell lung cancer (SCLC). Emerging pre-clinical data suggest that TEM8-targeting therapies may convert immunologically "cold" tumor microenvironments (TME) into "hot" milieu with greater responses to immune checkpoint inhibitors (ICIs).
METHODS: NextGen sequencing of DNA (592 genes or whole exome)/RNA (whole transcriptome) was performed on SCLC (N = 1404) and other NET (N = 1668) samples submitted to Caris Life Sciences (Phoenix, AZ). Samples were stratified by ANTXR1 expression quartiles (Q1 low, Q4 high). TME cell fractions were estimated by RNA deconvolution using quanTIseq. Real-world overall survival (OS) was assessed from insurance claim data.
RESULTS: The landscape of pathogenic gene mutations was similar among ANTXR1 Q1 vs Q4 tumors among SCLC and NET cohorts. The TME of SCLC and NET Q4 tumors comprised a greater fraction of B cells and M1/M2 macrophages and were more frequently classified as 'T cell-inflamed' based on a transcriptional signature predictive of response to ICI. However, OS from the start of ICI was similar between ANTXR1 Q1 and Q4 cohorts.
CONCLUSIONS: Increased B cell and M1/M2 macrophage infiltrate, along with T-cell inflamed status, associated with ANTXR1 Q4 TMEs suggest these patients with SCLC and NET may respond preferentially to ICI. A Phase 1 trial incorporating SVV-01 along with ICI is underway. Prospective investigation of molecular associations and clinical outcomes related to ANTXR1 expression in SCLC is warranted.

Keywords: ANTXR1; Molecular oncology; Neuroendocrine tumor; TEM8; Tumor microenvironment

DOI: https://doi.org/10.1016/j.ctarc.2026.101190