bims-necame 2025-07-13 papers

Issue of 2025–07–13
four papers selected by
Grigor Varuzhanyan, UCLA

J Clin Invest. 2025 Jul 08. pii: e185423. [Epub ahead of print]

NOTCH1 reverses immune suppression in small cell lung cancer through reactivation of STING.

Downregulation of antigen presentation and lack of immune infiltration are defining features of small cell lung cancer (SCLC) limiting response to immune checkpoint blockade (ICB). While a high MHC Class I, immune-inflamed subset benefits from ICB, underlying mechanisms of immune response in SCLC have yet to be elucidated. Here we show that in the landmark IMpower133 clinical trial high, but not low, NOTCH1 expression is significantly associated with longer survival with the addition of ICB to chemotherapy among ~80% of SCLC patients with neuroendocrine-enriched tumors (ASCL1-enriched, HR 0.39, P = 0.0012; NEUROD1-enriched, HR 0.44, P = 0.024). Overexpression or pharmacologic activation of NOTCH1 in ASCL1 and NEUROD1 SCLC cell lines dramatically upregulates MHC Class I through epigenetic reactivation of STING. In syngeneic mouse models, Notch1 activation reprograms SCLC tumors from immune-excluded to immune-inflamed, facilitating durable, complete responses with ICB combined with a STING agonist. STING1 expression is significantly enriched in high compared to low NOTCH1 expressing tumors in IMpower133 thereby validating our proposed mechanism. Our data reveal a previously undiscovered role for NOTCH1 as a critical driver of SCLC immunogenicity and a potential predictive biomarker for ICB in SCLC. NOTCH1 activation may be a therapeutic strategy to unleash anti-tumor immune responses in SCLC and other neuroendocrine cancers in which NOTCH1 is typically suppressed.

Keywords: Antigen; Biomarkers; Cancer immunotherapy; Cell biology; Immunology; Oncology

DOI: https://doi.org/10.1172/JCI185423

Res Sq. 2025 Jul 01. pii: rs.3.rs-6960266. [Epub ahead of print]

FOXM1 targeting alters AURKB activity and reshapes antitumor immunity to curb the progression of small cell lung cancer.

Md Arafat Khan, Parvez Khan, Mahek Fatima, Asad Ur Rehman, Laiba Anwar, Zahraa Wajih Alsafwani, Aatiya Ahmad, Mohammad Ali Abbas Zaidi, Jesse L Cox, Areem Zahid, Sameer Mohiuddin, Sung Hoon Kim, Juan A Santamaria-Barria, Imayavaramban Lakshmanan, Benita S Katzenellenbogen, John A Katzenellenbogen, Apar K Ganti, Surinder K Batra, Mohd Wasim Nasser.

Background Small cell lung cancer (SCLC) is a lethal lung malignancy and patients are often diagnosed with distant metastasis. Nearly all patients suffer from disease relapsing with inherent chemoresistance. Lack of targeted SCLC therapies further worsens disease outcomes, making it highly desirable to identify novel and effective therapeutic targets. Methods To search for potential therapeutic targets in SCLC, we analyzed publicly available single-cell and bulk RNA-sequencing (RNA-seq) data from normal, lung adenocarcinoma, and SCLC tumor tissues. To assess the targeting potential of FOXM1, we developed various in vitro models, including DOX-On-shFOXM1 (Tet-ON) inducible stable knockdown systems. Cisplatin resistant human and murine SCLC cell lines were generated to assess the role of FOXM1 in chemotherapy resistance. Immunoblotting, immunohistochemistry (IHC), and immuno-fluorescence were used to analyze the expression of FOXM1 and target proteins. ChIP-assay was used to study protein-gene interactions. Further, multicolor flow cytometry was employed to study the effect of FOXM1 inhibition on human T cells activation and differentiation. Subcutaneous xenograft and SCLC spontaneous (RPM: RB fl/fl ; TP53 fl/fl ; LSL-MYC T58A ) mouse models were used to evaluate the efficacy of FOXM1 inhibitors. Results Single-cell as well as bulk RNA-seq data revealed that FOXM1, an oncogenic transcription factor, is overexpressed in SCLC, and it was recapitulated in human and murine SCLC tissues and cell lines. Interestingly, chemo-resistant (CR) SCLC showed a substantially higher FOXM1 expression than naïve SCLC. Silencing FOXM1 genetically or pharmacologically by FOXM1 inhibitors revealed a marked reduction in cell viability, colony formation, migration and sphere formation in naïve and CR SCLC cells. Moreover, FOXM1 inhibition induced apoptosis and cell cycle arrest in SCLC cells. Furthermore, FOXM1 inhibition in combination with first-line platinum-based chemotherapy showed synergistic anticancer effects in both xenograft and RPM mouse models of SCLC. Our RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway, which is dysregulated in SCLC. Moreover, we found FOXM1 inhibition enhanced T cell activation and supported the differentiation of CD8 + cytotoxic T cells, and T cell-mediated killing of cancer cells. Conclusions Our study demonstrates that FOXM1 targeting using small molecule inhibitors has the potential to be a novel therapeutic strategy to combat SCLC progression including chemotherapeutic resistance and reshaping the anti-tumor immune response.

DOI: https://doi.org/10.21203/rs.3.rs-6960266/v1

Cancer Med. 2025 Jul;14(13): e71034

Midkine Promotes Tumor Growth and Attenuates the Effect of Cisplatin in Small Cell Lung Cancer.

Shotaro Ito, Jun Sakakibara-Konishi, Mineyoshi Sato, Tetsuaki Shoji, Megumi Furuta, Hirofumi Takahashi, Kosuke Tsuji, Daisuke Morinaga, Masahiro Kashima, Hidenori Kitai, Junko Kikuchi, Eiki Kikuchi, Kanako C Hatanaka, Yutaka Hatanaka, Kyoko Hida, Takuro Noguchi, Satoshi Konno.

PURPOSE: Small cell lung cancer (SCLC) is a highly aggressive disease associated with poor patient survival rates. The addition of an anti-programmed death ligand 1 antibody to platinum combination chemotherapy can improve its prognosis. However, only a few patients achieve a long-term response; thus, establishing new therapies for SCLC is crucial. Midkine (MDK) is a heparin-binding growth factor involved in various biological processes, including cell proliferation and chemotherapeutic resistance, in diverse cancers. MDK has garnered attention as a therapeutic and diagnostic target for several cancers; however, only a few studies have evaluated its expression and function in SCLC. This study aimed to evaluate the MDK expression in human SCLC tissue and human SCLC cell lines, and to clarify its function in tumorigenesis.
METHODS: MDK expression was analyzed in vitro and in vivo through ELISA, immunohistochemistry, and western blotting. Its effects on cell proliferation, as well as the effects of cisplatin, were evaluated using the MTT assay.
RESULTS: MDK was pathologically expressed in human SCLC tumor tissues but not in normal lung tissues. Serum MDK concentrations in patients with SCLC reflected the SCLC tumor burden and were correlated with response to treatment. Moreover, MDK induced cell proliferation and attenuated the effects of cisplatin in SCLC cell lines. An MDK inhibitor and cisplatin exerted synergistic antitumor effects both in vitro and in vivo. Furthermore, MDK positively regulated the AKT pathway.
CONCLUSION: Our findings indicate that MDK promotes cell proliferation and chemotherapeutic resistance by activating the AKT pathway in SCLC cells. Therefore, MDK may be a potential therapeutic and diagnostic target for SCLC.

Keywords: AKT; Midkine; biomarker; small cell lung cancer; therapeutic target; tumor progression

DOI: https://doi.org/10.1002/cam4.71034

Sci Rep. 2025 Jul 09. 15(1): 24632

Associations between four insulin resistance (IR) surrogates and the risk of small cell lung cancer (SCLC).

Yuedong Wang, Kun Zhang, Zhifei Xin, Wenjian Hu, Wenbo Wu, Yi Ma, Di Yao, Mutong Wang, Xiaopeng Zhang.

Insulin resistance (IR) has been shown to be correlated with increased cancer risk. Nevertheless, few studies have explored the relationship between IR and small cell lung cancer (SCLC). The triglyceride glucose (TyG) index, TyG index with body mass index (TyG-BMI), triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C), and metabolic score for IR (METS-IR) are recognized as reliable indicators for evaluating IR. In our investigation, 235 patients with pathologically confirmed SCLC were enrolled, along with 235 healthy individuals matched for age and sex as controls. Univariate binary logistic regression analyses revealed a significant association between elevated levels of all IR surrogates and the risk of SCLC. This finding persisted even after adjusting for other established high-risk factors. Concurrently, a progressive increase in the incidence of SCLC was observed across the tertiles of the TyG index, TyG-BMI, TG/HDL-C, and METS-IR. Furthermore, this article is the first to conclude that the four IR surrogates did not significantly differ across different stages of SCLC, implying that IR might exert a greater influence on the onset than on the progression of SCLC. Among these factors, TG/HDL-C has emerged as the most effective predictor of SCLC. Consequently, lifestyle modifications and pharmacological interventions should be actively pursued in individuals with IR to mitigate their risk of developing SCLC. Our findings also offer a promising avenue for the identification of novel therapeutic targets.

Keywords: Insulin resistance; Small cell lung cancer

DOI: https://doi.org/10.1038/s41598-025-09548-0