Identification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer

被引：14

作者：

Maroni, Giorgia ^{[1
,2
,3
]}

Bassal, Mahmoud A. ^{[1
,2
]}

Krishnan, Indira ^{[2
]}

Fhu, Chee Wai ^{[1
]}

Savova, Virginia ^{[4
]}

Zilionis, Rapolas ^{[4
,5
]}

Maymi, Valerie A. ^{[6
,7
]}

Pandell, Nicole ^{[6
,7
]}

Csizmadia, Eva ^{[6
]}

Zhang, Junyan ^{[2
]}

Storti, Barbara ^{[8
,9
]}

Castano, Julio ^{[10
]}

Panella, Riccardo ^{[2
,11
]}

Li, Jia ^{[1
]}

Gustafson, Corinne E. ^{[12
,13
]}

Fox, Sam ^{[12
,13
]}

Levy, Rachel D. ^{[12
,13
]}

Meyerovitz, Claire, V ^{[12
,13
]}

Tramontozzi, Peter J. ^{[12
,13
]}

Vermilya, Kimberly ^{[12
,13
]}

De Rienzo, Assunta ^{[2
,12
,13
]}

Crucitta, Stefania ^{[14
]}

Basseres, Daniela S. ^{[15
]}

Weetall, Marla ^{[16
]}

Branstrom, Art ^{[16
]}

Giorgetti, Alessandra ^{[17
,18
]}

Ciampi, Raffaele ^{[19
]}

Del Re, Marzia ^{[20
]}

Danesi, Romano ^{[14
]}

Bizzarri, Ranieri ^{[8
,9
,21
]}

Yang, Henry ^{[1
]}

Kocher, Olivier ^{[2
,6
]}

Klein, Allon M. ^{[4
]}

Welner, Robert S. ^{[22
]}

Bueno, Raphael ^{[2
,12
,13
]}

Magli, Maria Cristina ^{[3
]}

Clohessy, John G. ^{[2
,6
,7
]}

Ali, Azhar ^{[1
]}

Tenen, Daniel G. ^{[1
,2
,23
]}

Levantini, Elena ^{[2
,3
,6
,23
]}

机构：

[1] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Natl Res Council CNR, Inst Biomed Technol, Area Ric Pisa, Pisa, Italy

[4] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

[5] Vilnius Univ, Life Sci Ctr, Inst Biotechnol, Vilnius, Lithuania

[6] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[7] Dana Farber Harvard Canc Ctr, Beth Israel Deaconess Canc Ctr, Preclin Murine Pharmacogenet Core, Boston, MA USA

[8] Scuola Normale Super Pisa, NEST, Pisa, Italy

[9] CNR, Ist Nanosci, Pisa, Italy

[10] Banc Sang & Teixits BST, Platform Immunotherapy BST Hosp Clin, Barcelona, Spain

[11] Desert Res Inst, Ctr Genom Med, Reno, NV USA

[12] Brigham & Womens Hosp, Lung Ctr, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA

[13] Brigham & Womens Hosp, Int Mesothelioma Program, 75 Francis St, Boston, MA 02115 USA

[14] Univ Pisa, Dept Clin & Expt Med, Unit Clin Pharmacol & Pharmacogenet, Pisa, Italy

[15] Univ Sao Paulo, Chem Inst, Biochem Dept, Sao Paulo, Brazil

[16] PTC Therapeut, 100 Corp Court, Corporate Court, NJ USA

[17] Univ Barcelona, Fac Med & Hlth Sci, Dept Pathol & Expt Therapeut, Cell Biol Unit, Barcelona, Spain

[18] Inst Invest Biomed Bellvitge IDIBELL, Regenerat Med Program, Stem Cell Biol & Leukemiogenesis Grp, Barcelona, Spain

[19] Univ Hosp Pisa, Dept Clin & Expt Med, Endocrine Unit, Pisa, Italy

[20] Univ Hosp Pisa, Dept Lab Med, Unit Clin Pharmacol & Pharmacogenet, Pisa, Italy

[21] Univ Pisa, Dept Surg Med & Mol Pathol & Crit Care Med, Pisa, Italy

[22] Univ Alabama Birmingham, Dept Med, Hemathol Oncol, Birmingham, AL 35294 USA

[23] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

来源：

COMMUNICATIONS BIOLOGY | 2021年 / 4卷 / 01期

基金：

新加坡国家研究基金会; 英国医学研究理事会; 巴西圣保罗研究基金会;

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; BMI-1; ONCOPROTEIN; GENE-EXPRESSION; MICROARRAY ANALYSIS; OVEREXPRESSION; PROGRESSION; CARCINOMA; ATLAS;

D O I：

10.1038/s42003-021-01897-6

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas. Maroni, Bassal, Krishnan et al. characterise human non-small cell lung cancer (NSCLC) carrying Kras-mutations by single-cell RNA sequencing. They identify a tumour-specific population that is conserved in mice and responds to the drug, PTC596, which is currently in clinical trials and may offer a potential avenue for treating aggressive NSCLC expressing mutated Kras.

引用

页数：15

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