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

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Maroni, Giorgia ; Bassal, Mahmoud A. ; Krishnan, Indira ; Fhu, Chee Wai ; Savova, Virginia ; Zilionis, Rapolas ; Maymi, Valerie A. ; Pandell, Nicole ; Csizmadia, Eva ; Zhang, Junyan ; Storti, Barbara ; Castano, Julio ; Panella, Riccardo ; Li, Jia ; Gustafson, Corinne E. ; Fox, Sam ; Levy, Rachel D. ; Meyerovitz, Claire, V ; Tramontozzi, Peter J. ; Vermilya, Kimberly ; De Rienzo, Assunta ; Crucitta, Stefania ; Basseres, Daniela S. ; Weetall, Marla ; Branstrom, Art ; Giorgetti, Alessandra ; Ciampi, Raffaele ; Del Re, Marzia ; Danesi, Romano ; Bizzarri, Ranieri ; Yang, Henry ; Kocher, Olivier ; Klein, Allon M. ; Welner, Robert S. ; Bueno, Raphael ; Magli, Maria Cristina ; Clohessy, John G. ; Ali, Azhar ; Tenen, Daniel G. ; Levantini, Elena

• Tipo de documento: Artigo Científico
• Fonte: COMMUNICATIONS BIOLOGY; v. 4, n. 1, p. 15-pg., 2021-04-14.

Resumo

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. (AU)

• Processo FAPESP: 16/19757-2 - EXPLORANDO A QUINASE IKKbeta COMO UM ALVO TERAPÊUTICO ANTI-METASTÁTICO NO CÂNCER DE PULMÃO INDUZIDO PELO ONCOGENE KRAS
• Beneficiário: Daniela Sanchez Basseres
• Modalidade de apoio: Auxílio à Pesquisa - Regular