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A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer.

ABSTRACT: Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. SIGNIFICANCE: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS-driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models.This article is highlighted in the In This Issue feature, p. 1601.

SUBMITTER: Cai H

PROVIDER: S-EPMC8292166 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A functional taxonomy of tumor suppression in oncogenic KRAS-driven lung cancer

Project description:Extensive cancer genotyping has identified a large number of putative tumor suppressor genes. However, genome sequencing data alone is insufficient to uncover the importance or the specific functional roles of these genes during carcinogenesis. It is generally unclear whether more frequently mutated tumor suppressors are also more consequential for tumor development. Furthermore, whether tumor suppressors restrict the rate of tumor growth, decrease the probability of incipient tumorigenesis, or limit the emergence of particularly fast-growing clones remains unknown for even the most well-studied tumor suppressors. Here we use a multiplexed autochthonous mouse model of oncogenic Kras-driven human lung adenocarcinoma to quantify the impact of forty-eight known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We discover many previously understudied functional tumor suppressors that constrain multiple aspects of carcinogenesis in vivo. Inactivation of some genes substantially elevates tumor growth rate, while the inactivation of others increases the probability of tumor initiation and/or the emergence of exceptionally large tumors. While some known and novel functional tumor suppressor genes exert particularly strong effects during specific phases of tumorigenesis, others impact multiple facets of tumor development. These direct and causal analyses uncover an unexpectedly complex functional landscape of tumor suppression. This map of carcinogenesis has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression.

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A functional taxonomy of tumor suppression in oncogenic KRAS-driven lung cancer

Project description:A functional taxonomy of tumor suppression in oncogenic KRAS-driven lung cancer

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Project description:Recent advances in molecular biology and the resultant identification of driver oncogenes have achieved major progress in precision medicine for non-small-cell lung cancer (NSCLC). v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) is the most common driver in NSCLC, and targeting KRAS is considerably important. The recent discovery of covalent KRAS G12C inhibitors offers hope for improving the prognosis of NSCLC patients, but the development of combination therapies corresponding to tumor characteristics is still required given the vast heterogeneity of KRAS-mutated NSCLC. In this review, we summarize the current understanding of KRAS mutations regarding the involvement of malignant transformation and describe the preclinical and clinical evidence for targeting KRAS-mutated NSCLC. We also discuss the mechanisms of resistance to KRAS G12C inhibitors and possible combination treatment strategies to overcome this drug resistance.

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AGO2 promotes tumor progression in KRAS-driven mouse models of non-small cell lung cancer.

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Ezh2 Acts as a Tumor Suppressor in Kras-driven Lung Adenocarcinoma.

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