Cells Lacking the <i>RB1</i> Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival

Oser, Matthew G.; Fonseca, Raquel; Chakraborty, Abhishek A.; Brough, Rachel; Spektor, Alexander; Jennings, Rebecca B.; Flaifel, Abdallah; Novak, Jesse; Gulati, Aditi; Buss, Elizabeth; Younger, Scott T.; McBrayer, Samuel K.; Cowley, Glenn S.; Bonal, Dennis M.; Nguyen, Quang Dé; Brullé-Soumaré, Laura; Taylor, Paula; Cairo, Stefano; Ryan, Colm J.; Pease, Elizabeth J.; Maratea, Kim; Travers, Jon; Root, David E.; Signoretti, Sabina; Pellman, David; Ashton, Susan; Lord, Christopher J.; Barry, Simon T.; Kaelin, William G.

doi:10.1158/2159-8290.cd-18-0389

Cited by 126 publications

(99 citation statements)

References 49 publications

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“…Recent studies implicate Aurora kinases (AURKA or AURKB) that regulate mitotic spindle assembly and chromosome segregation as alternative therapeutic targets. Independent CRISPR/Cas9 (Oser et al, 2019) and drug screening assays (Gong et al, 2019) using Rb1-deficient classical SCLC cell lines simultaneously identified a unique dependence upon AURK for survival. In these studies, AURK inhibitors potently suppressed the growth of Rb1-negative SCLC cells but had no effect on Rb1-positive lung cancer cells (including the EGFR mutant cell lines H1975 and PC9).…”

Section: Targeting Unique Cell Cycle Vulnerabilities Created By Rb1 Lossmentioning

confidence: 99%

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

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Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called "bypass activation"). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.

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Section: Targeting Unique Cell Cycle Vulnerabilities Created By Rb1 Lossmentioning

confidence: 99%

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

et al. 2020

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“…However, we may be able to indirectly target Sp1 in cancer by identifying and exploiting its synthetic lethal dependencies. Several recent studies have identified synthetic lethal interactions during mitosis in other contexts (Oser et al, 2019;van der Lelij et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

Flashner

Swift

Sowash

et al. 2020

Preprint

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Mitotic chromosome assembly is essential for faithful chromosome segregation. Despite their salient role directing interphase chromatin organization, little is known about how transcription factors mediate this process during mitosis. Here, we characterize a mitosis-specific role for transcription factor specificity protein 1 (Sp1). Sp1 localizes to mitotic centromeres and auxininduced rapid Sp1 degradation results in chromosome segregation errors and aberrant mitotic progression. These defects are driven by anomalous mitotic chromosome assembly. Sp1 degradation results in chromosome condensation defects through reduced condensin complex I localization. Sp1 also mediates the localization and activation of Aurora B kinase early in mitosis, which is essential for condensin complex I recruitment. Underscoring the clinical significance of our findings, aberrant Sp1 expression correlates with aneuploidy in several human cancers, including kidney renal papillary cell carcinoma, ovarian serous cystadenocarcinoma, mesothelioma, cholangiocarcinoma, and hepatocellular carcinoma. Our results suggest that Sp1 protects genomic integrity during mitosis by promoting chromosome assembly.

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“…Mechanistically, Aurora kinase A which is encoded by AURKA promotes mitosis entry through phosphorylating and activating PLK1 [88]. Aurora kinase B serves as a component of the chromosomal passenger complex to regulate chromosome segregation and cytokinesis in mitosis [89]. The gene encoding Aurora kinase A is frequently amplified in various cancer types, including SCLC, highlighting it as a potent therapeutic target in cancer treatment.…”

Section: Aurora Kinase As a Therapeutic Target In The Treatment Of Sclcmentioning

confidence: 99%

Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

Bian

Lin

2019

Cancers

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Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

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Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival

Cited by 126 publications

References 49 publications

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

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