Intratumor heterogeneity in KRAS signaling shapes treatment resistance
Summary: KRAS mutations are linked to some of the deadliest forms of cancer. Pharmacological studies suggest that co-targeting KRAS with feedback/bypass pathways could lead to enhanced anti-tumor activity. The underlying premise is that cancers display a deep-rooted hypersensitivity to KRAS inactiva...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422402889X |
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| author | Oleksi Petrenko Varvara Kirillov Stephen D'Amico Nancy C. Reich |
| author_facet | Oleksi Petrenko Varvara Kirillov Stephen D'Amico Nancy C. Reich |
| author_sort | Oleksi Petrenko |
| collection | DOAJ |
| description | Summary: KRAS mutations are linked to some of the deadliest forms of cancer. Pharmacological studies suggest that co-targeting KRAS with feedback/bypass pathways could lead to enhanced anti-tumor activity. The underlying premise is that cancers display a deep-rooted hypersensitivity to KRAS inactivation. Here, we investigate the role of intratumor heterogeneity in pancreatic ductal adenocarcinoma, focusing on oncogenic KRAS addiction and treatment resistance. Integrated analysis of single-cell and bulk RNA sequencing data reveals that most tumors display a mixture of cells with vastly different degrees of KRAS dependency. We identify distinct cell populations that vary in their gene expression patterns pertaining to the predicted level of KRAS signaling activity, cell growth, and differentiation commitment within each tumor. Selective targeting of mutant KRAS suppresses the growth of tumor cells with high RAS/mitogen-activated protein kinase (MAPK) activity while sparing pre-existing subsets with low RAS signaling activity, necessitating alternative treatments. Combination immunotherapy leads to durable tumor regression in preclinical models. |
| format | Article |
| id | doaj-art-2a156841bd93487ebbc8a3b21f5abfe8 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-2a156841bd93487ebbc8a3b21f5abfe82025-01-18T05:05:03ZengElsevieriScience2589-00422025-02-01282111662Intratumor heterogeneity in KRAS signaling shapes treatment resistanceOleksi Petrenko0Varvara Kirillov1Stephen D'Amico2Nancy C. Reich3Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USA; Corresponding authorDepartment of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USADepartment of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USADepartment of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USA; Corresponding authorSummary: KRAS mutations are linked to some of the deadliest forms of cancer. Pharmacological studies suggest that co-targeting KRAS with feedback/bypass pathways could lead to enhanced anti-tumor activity. The underlying premise is that cancers display a deep-rooted hypersensitivity to KRAS inactivation. Here, we investigate the role of intratumor heterogeneity in pancreatic ductal adenocarcinoma, focusing on oncogenic KRAS addiction and treatment resistance. Integrated analysis of single-cell and bulk RNA sequencing data reveals that most tumors display a mixture of cells with vastly different degrees of KRAS dependency. We identify distinct cell populations that vary in their gene expression patterns pertaining to the predicted level of KRAS signaling activity, cell growth, and differentiation commitment within each tumor. Selective targeting of mutant KRAS suppresses the growth of tumor cells with high RAS/mitogen-activated protein kinase (MAPK) activity while sparing pre-existing subsets with low RAS signaling activity, necessitating alternative treatments. Combination immunotherapy leads to durable tumor regression in preclinical models.http://www.sciencedirect.com/science/article/pii/S258900422402889XCell biologyCancerOmics |
| spellingShingle | Oleksi Petrenko Varvara Kirillov Stephen D'Amico Nancy C. Reich Intratumor heterogeneity in KRAS signaling shapes treatment resistance iScience Cell biology Cancer Omics |
| title | Intratumor heterogeneity in KRAS signaling shapes treatment resistance |
| title_full | Intratumor heterogeneity in KRAS signaling shapes treatment resistance |
| title_fullStr | Intratumor heterogeneity in KRAS signaling shapes treatment resistance |
| title_full_unstemmed | Intratumor heterogeneity in KRAS signaling shapes treatment resistance |
| title_short | Intratumor heterogeneity in KRAS signaling shapes treatment resistance |
| title_sort | intratumor heterogeneity in kras signaling shapes treatment resistance |
| topic | Cell biology Cancer Omics |
| url | http://www.sciencedirect.com/science/article/pii/S258900422402889X |
| work_keys_str_mv | AT oleksipetrenko intratumorheterogeneityinkrassignalingshapestreatmentresistance AT varvarakirillov intratumorheterogeneityinkrassignalingshapestreatmentresistance AT stephendamico intratumorheterogeneityinkrassignalingshapestreatmentresistance AT nancycreich intratumorheterogeneityinkrassignalingshapestreatmentresistance |