scholarly journals An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer

2020 ◽  
Author(s):  
Athea Vichas ◽  
Naomi T. Nkinsi ◽  
Amanda Riley ◽  
Phoebe C.R. Parrish ◽  
Fujiko Duke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Hippo Pathway ◽  
Spindle Assembly ◽  
Human Lung Cancer ◽  
Precision Oncology ◽  
Cancer Driver ◽  
Molecular Alterations ◽  
Pathway Gene ◽  
Genome Wide

ABSTRACTAdvances in precision oncology have transformed cancer therapy from broadly-applied cytotoxic therapy to personalized treatments based on each tumor’s unique molecular alterations. Here we investigate the oncogene-specific dependencies conferred by lung cancer driver variants of KRAS, EGFR, and RIT1. Integrative analysis of genome-wide CRISPR screens in isogenic cell lines identified shared and unique vulnerabilities of each oncogene. The non-identical landscape of dependencies underscores the importance of genotype-guided therapies to maximize tumor responses. Combining genetic screening data with small molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. This sensitivity may be related to a novel role of RIT1 in mitosis; we find that oncogenic RIT1M90I alters mitotic timing via weakening of the spindle assembly checkpoint. In addition, we uncovered a specific cooperation of mutant RIT1 with loss of Hippo pathway genes. In human lung cancer, RIT1 mutations and amplifications frequently co-occur with loss of Hippo pathway gene expression. These results provide the first genome-wide atlas of oncogenic RIT1-cooperating factors and genetic dependencies and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.

scholarly journals Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Athea Vichas ◽  
Amanda K. Riley ◽  
Naomi T. Nkinsi ◽  
Shriya Kamlapurkar ◽  
Phoebe C. R. Parrish ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Genetic Data ◽  
Multiple Models ◽  
Ras Pathway ◽  
Functional Interactions ◽  
Genome Wide ◽  
A Genome ◽  
Mutant Cells

AbstractCRISPR-based cancer dependency maps are accelerating advances in cancer precision medicine, but adequate functional maps are limited to the most common oncogenes. To identify opportunities for therapeutic intervention in other rarer subsets of cancer, we investigate the oncogene-specific dependencies conferred by the lung cancer oncogene, RIT1. Here, genome-wide CRISPR screening in KRAS, EGFR, and RIT1-mutant isogenic lung cancer cells identifies shared and unique vulnerabilities of each oncogene. Combining this genetic data with small-molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. Oncogenic RIT1M90I weakens the spindle assembly checkpoint and perturbs mitotic timing, resulting in sensitivity to Aurora A inhibition. In addition, we observe synergy between mutant RIT1 and activation of YAP1 in multiple models and frequent nuclear overexpression of YAP1 in human primary RIT1-mutant lung tumors. These results provide a genome-wide atlas of oncogenic RIT1 functional interactions and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.

scholarly journals Tank Binding Kinase 1 modulates spindle assembly checkpoint components to regulate mitosis in breast and lung cancer cells

2021 ◽  
Vol 1868 (3) ◽  
pp. 118929
Author(s):  
Meenu Maan ◽  
Neha Jaiswal Agrawal ◽  
Jaya Padmanabhan ◽  
Christelle Colin Leitzinger ◽  
Yainyrette Rivera-Rivera ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Lung Cancer Cells

Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations

2022 ◽  
Author(s):  
Aaron C. Tan ◽  
Daniel S. W. Tan
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Braf V600e ◽  
Standards Of Care ◽  
Molecular Testing ◽  
Precision Oncology ◽  
Early Stage Disease ◽  
Molecular Alterations ◽  
Oncogenic Driver ◽  
Exon 20

Lung cancer has traditionally been classified by histology. However, a greater understanding of disease biology and the identification of oncogenic driver alterations has dramatically altered the therapeutic landscape. Consequently, the new classification paradigm of non–small-cell lung cancer is further characterized by molecularly defined subsets actionable with targeted therapies and the treatment landscape is becoming increasingly complex. This review encompasses the current standards of care for targeted therapies in lung cancer with driver molecular alterations. Targeted therapies for EGFR exon 19 deletion and L858R mutations, and ALK and ROS1 rearrangements are well established. However, there is an expanding list of approved targeted therapies including for BRAF V600E, EGFR exon 20 insertion, and KRAS G12C mutations, MET exon 14 alterations, and NTRK and RET rearrangements. In addition, there are numerous other oncogenic drivers, such as HER2 exon 20 insertion mutations, for which there are emerging efficacy data for targeted therapies. The importance of diagnostic molecular testing, intracranial efficacy of novel therapies, the optimal sequencing of therapies, role for targeted therapies in early-stage disease, and future directions for precision oncology approaches to understand tumor evolution and therapeutic resistance are also discussed.

scholarly journals ARHGEF17 is an essential spindle assembly checkpoint factor that targets Mps1 to kinetochores

2016 ◽  
Vol 212 (6) ◽  
pp. 647-659 ◽  
Author(s):  
Mayumi Isokane ◽  
Thomas Walter ◽  
Robert Mahen ◽  
Bianca Nijmeijer ◽  
Jean-Karim Hériché ◽  
...  
Keyword(s):  
Rna Interference ◽  
Mitotic Spindle ◽  
Spindle Assembly Checkpoint ◽  
Genome Instability ◽  
Quantitative Imaging ◽  
Direct Interaction ◽  
Spindle Assembly ◽  
Mitotic Exit ◽  
Genome Wide ◽  
A Genome

To prevent genome instability, mitotic exit is delayed until all chromosomes are properly attached to the mitotic spindle by the spindle assembly checkpoint (SAC). In this study, we characterized the function of ARHGEF17, identified in a genome-wide RNA interference screen for human mitosis genes. Through a series of quantitative imaging, biochemical, and biophysical experiments, we showed that ARHGEF17 is essential for SAC activity, because it is the major targeting factor that controls localization of the checkpoint kinase Mps1 to the kinetochore. This mitotic function is mediated by direct interaction of the central domain of ARHGEF17 with Mps1, which is autoregulated by the activity of Mps1 kinase, for which ARHGEF17 is a substrate. This mitosis-specific role is independent of ARHGEF17’s RhoGEF activity in interphase. Our study thus assigns a new mitotic function to ARHGEF17 and reveals the molecular mechanism for a key step in SAC establishment.

scholarly journals KIAA0101 and UbcH10 interact to regulate non-small cell lung cancer cell proliferation by disrupting the function of the spindle assembly checkpoint

2020 ◽  
Author(s):  
Han Lei ◽  
Kun Wang ◽  
Tongying Jiang ◽  
Jingjing Lu ◽  
Xue Dong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Small Cell ◽  
Binding Motif ◽  
Small Cell Lung

Abstract Background: Chromosome mis-segregation caused by spindle assembly checkpoint (SAC) dysfunction during mitosis is an important pathogenic factor in cancer, and modulating SAC function has emerged as a potential novel therapy for non-small cell lung cancer (NSCLC). UbcH10 is considered to be associated with SAC function and the pathological types and clinical grades of NSCLC. KIAA0101, which contains a highly conserved proliferating cell nuclear antigen (PCNA)-binding motif that is involved in DNA repair in cancer cells, plays an important role in the regulation of SAC function in NSCLC cells, and bioinformatics predictions showed that this regulatory role is related to UbcH10. We hypothesized KIAA0101 and UbcH10 interact to mediate SAC dysfunction and neoplastic transformation during the development of USCLC. Methods: NSCLC cell lines were used to investigate the spatial-temporal correlation between UbcH10 and KIAA0101 expression and the downstream effects of modulating their expression were evaluated. Further immunoprecipitation assays were used to investigate the possible mechanism underlying the correlation between UbcH10 and KIAA0101. Eventually, the effect of modulating UbcH10 and KIAA010 on tumor growth and its possible mechanisms were explored through in vivo tumor-bearing models.Results: In this study, we demonstrated that both UbcH10 and KIAA0101 were upregulated in NSCLC tissues and cells and that their expression levels were correlated in a spatial and temporal manner. Importantly, UbcH10 and KIAA0101 coordinated to mediate the premature degradation of various SAC components to cause further SAC dysfunction and neoplastic proliferation. Moreover, tumor growth in vivo was significantly inhibited by silencing UbcH10 and KIAA0101 expression. Conclusions: KIAA0101 and UbcH10 interact to cause SAC dysfunction, chromosomal instability and malignant proliferation in NSCLC, suggesting that UbcH10 and KIAA0101 are potential therapeutic targets for the treatment of NSCLC by ameliorating SAC function.

scholarly journals The Role of the Liquid Biopsy in Decision-Making for Patients with Non-Small Cell Lung Cancer

2020 ◽  
Vol 9 (11) ◽  
pp. 3674
Author(s):  
D. Akhoundova ◽  
J. Mosquera Martinez ◽  
L. E. Musmann ◽  
C. Britschgi ◽  
C. Rütsche ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Practice ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Clinical Management ◽  
Circulating Tumor Dna ◽  
Precision Oncology ◽  
Liquid Biopsies ◽  
Lung Cancer Patients ◽  
Molecular Alterations

Liquid biopsy is a rapidly emerging tool of precision oncology enabling minimally invasive molecular diagnostics and longitudinal monitoring of treatment response. For the clinical management of advanced stage lung cancer patients, detection and quantification of circulating tumor DNA (ctDNA) is now widely adopted into clinical practice. Still, interpretation of results and validation of ctDNA-based treatment decisions remain challenging. We report here our experience implementing liquid biopsies into the clinical management of lung cancer. We discuss advantages and limitations of distinct ctDNA assay techniques and highlight our approach to the analysis of recurrent molecular alterations found in lung cancer. Moreover, we report three exemplary clinical cases illustrating the complexity of interpreting liquid biopsy results in clinical practice. These cases underscore the potential and current limitations of liquid biopsy, focusing on the difficulty of interpreting discordant findings. In our view, despite all current limitations, the analysis of ctDNA in lung cancer patients is an essential and highly versatile complementary diagnostic tool for the clinical management of lung cancer patients in the era of precision oncology.

scholarly journals KIAA0101 and UbcH10 interact to regulate non-small cell lung cancer cell proliferation by disrupting the function of the spindle assembly checkpoint

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Han Lei ◽  
Kun Wang ◽  
Tongying Jiang ◽  
Jingjing Lu ◽  
Xue Dong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Small Cell ◽  
Binding Motif ◽  
Small Cell Lung

Abstract Background Chromosome mis-segregation caused by spindle assembly checkpoint (SAC) dysfunction during mitosis is an important pathogenic factor in cancer, and modulating SAC function has emerged as a potential novel therapy for non-small cell lung cancer (NSCLC). UbcH10 is considered to be associated with SAC function and the pathological types and clinical grades of NSCLC. KIAA0101, which contains a highly conserved proliferating cell nuclear antigen (PCNA)-binding motif that is involved in DNA repair in cancer cells, plays an important role in the regulation of SAC function in NSCLC cells, and bioinformatics predictions showed that this regulatory role is related to UbcH10. We hypothesized KIAA0101 and UbcH10 interact to mediate SAC dysfunction and neoplastic transformation during the development of USCLC. Methods NSCLC cell lines were used to investigate the spatial-temporal correlation between UbcH10 and KIAA0101 expression and the downstream effects of modulating their expression were evaluated. Further immunoprecipitation assays were used to investigate the possible mechanism underlying the correlation between UbcH10 and KIAA0101. Eventually, the effect of modulating UbcH10 and KIAA010 on tumor growth and its possible mechanisms were explored through in vivo tumor-bearing models. Results In this study, we demonstrated that both UbcH10 and KIAA0101 were upregulated in NSCLC tissues and cells and that their expression levels were correlated in a spatial and temporal manner. Importantly, UbcH10 and KIAA0101 coordinated to mediate the premature degradation of various SAC components to cause further SAC dysfunction and neoplastic proliferation. Moreover, tumor growth in vivo was significantly inhibited by silencing UbcH10 and KIAA0101 expression. Conclusions KIAA0101 and UbcH10 interact to cause SAC dysfunction, chromosomal instability and malignant proliferation in NSCLC, suggesting that UbcH10 and KIAA0101 are potential therapeutic targets for the treatment of NSCLC by ameliorating SAC function.

scholarly journals KIAA0101 and UbcH10 interact to regulate non-small cell lung cancer cell proliferation by disrupting the function of the spindle assembly checkpoint

2020 ◽  
Author(s):  
Han Lei ◽  
Kun Wang ◽  
Tongying Jiang ◽  
Jingjing Lu ◽  
Xue Dong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Small Cell ◽  
Binding Motif ◽  
Small Cell Lung

Abstract Background Chromosome mis-segregation caused by spindle assembly checkpoint (SAC) dysfunction during mitosis is an important pathogenic factor in cancer, and modulating SAC function has emerged as a potential novel therapy for non-small cell lung cancer (NSCLC). UbcH10 is considered to be associated with SAC function and the pathological types and clinical grades of NSCLC. KIAA0101, which contains a highly conserved proliferating cell nuclear antigen (PCNA)-binding motif that is involved in DNA repair in cancer cells, plays an important role in the regulation of SAC function in NSCLC cells, and bioinformatics predictions showed that this regulatory role is related to UbcH10. We hypothesized KIAA0101 and UbcH10 interact to mediate SAC dysfunction and neoplastic transformation during the development of USCLC. Methods NSCLC cell lines were used to investigate the spatial-temporal correlation between UbcH10 and KIAA0101 expression and the downstream effects of modulating their expression were evaluated. Further immunoprecipitation assays were used to investigate the possible mechanism underlying the correlation between UbcH10 and KIAA0101. Eventually, the effect of modulating UbcH10 and KIAA010 on tumor growth and its possible mechanisms were explored through in vivo tumor-bearing models. Results In this study, we demonstrated that both UbcH10 and KIAA0101 were upregulated in NSCLC tissues and cells and that their expression levels were correlated in a spatial and temporal manner. Importantly, UbcH10 and KIAA0101 coordinated to mediate the premature degradation of various SAC components to cause further SAC dysfunction and neoplastic proliferation. Moreover, tumor growth in vivo was significantly inhibited by silencing UbcH10 and KIAA0101 expression. Conclusions KIAA0101 and UbcH10 interact to cause SAC dysfunction, chromosomal instability and malignant proliferation in NSCLC, suggesting that UbcH10 and KIAA0101 are potential therapeutic targets for the treatment of NSCLC by ameliorating SAC function.

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