ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer

被引：0

作者：

Gutierrez, Mirian ^{[1
]}

Zamora, Irene ^{[1
]}

Iriarte, Raquel ^{[1
]}

Pajares, Maria Jose ^{[1
,2
]}

Yang, Qian ^{[3
]}

Qian, Chen ^{[4
]}

Otegui, Nerea ^{[5
]}

Fernandez-Irigoyen, Joaquin ^{[1
,2
,6
]}

Santamaria, Enrique ^{[1
,2
,6
]}

Alcala, Nicolas ^{[7
]}

Sexton-Oates, Alexandra ^{[7
]}

Fernandez-Cuesta, Lynnette ^{[7
]}

Barajas, Miguel ^{[1
,2
]}

Calvo, Alfonso ^{[5
,8
,9
]}

Montuenga, Luis M. ^{[5
,8
,9
]}

Knudsen, Beatrice ^{[10
]}

You, Sungyong ^{[3
,4
]}

Freeman, Michael R. ^{[3
]}

Encio, Ignacio ^{[1
,2
]}

Rotinen, Mirja ^{[1
,2
]}

机构：

[1] Publ Univ Navarre UPNA, Dept Hlth Sci, Pamplona, Spain

[2] Navarre Inst Hlth Res IdiSNA, Pamplona, Navarre, Spain

[3] Cedars Sinai Med Ctr, Dept Urol & Biomed Sci, Los Angeles, CA USA

[4] Cedars Sinai Med Ctr, Dept Computat Biomed, Los Angeles, CA USA

[5] Univ Navarra, Ctr Appl Med Res, CIMA, Pamplona 31008, Navarra, Spain

[6] Hosp Univ Navarra HUN, Prote Unit, Clin Neuroprote Lab, Navarrabiomed, Pamplona, Navarre, Spain

[7] World Hlth Org IARC WHO, Genom Epidemiol Branch GEM, Int Agcy Res Canc, Rare Canc Genom Team RCG, Lyon, France

[8] Univ Navarra, Sch Med, Dept Pathol Anat & Physiol, Pamplona, Spain

[9] CIBERONC, Madrid, Spain

[10] Univ Utah, Dept Pathol, Salt Lake City, UT USA

来源：

MOLECULAR MEDICINE | 2025年 / 31卷 / 01期

关键词：

ONECUT2; SCLC; Tumor heterogeneity; Phenotypic plasticity; Therapeutic target; SUBTYPES; HETEROGENEITY; EXPRESSION; PROFILES; PLATFORM; PATHWAY; MODELS; TUMORS; YAP1;

D O I：

10.1186/s10020-025-01267-6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Small cell lung cancer (SCLC) is a highly aggressive malignancy with extremely poor prognosis. SCLC cells exhibit high plasticity and can progress from neuroendocrine (NE) to non-NE phenotypes. This dynamic evolution promotes treatment resistance and relapses, representing a challenge for targeted therapies in this elusive disease. Here we identify the transcription factor ONECUT2 (OC2) as a driver of plasticity in SCLC, leading to non-NE transcriptional states. OC2 is highly expressed in SCLC tumors compared to normal lung tissue and its expression is associated with heightened clinical stage and lymph node metastasis. We show that OC2 is a repressor of ASCL1, the NE master regulator transcription factor. In addition, OC2 upregulates non-NE programs through activation of c-MYC and Notch signaling. We also demonstrate that OC2 is required for growth and survival of SCLC cells and that it can be targeted with a small molecule inhibitor that acts synergistically with the standard combination of cisplatin and etoposide, providing a novel therapeutic strategy for OC2 active SCLC tumors.

引用

页数：16

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