NOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition.

Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian cancer with high fatality rates in advanced stages due to its chemoresistant properties. LGSOC is characterized by activation of MAPK signaling, and recent clinical trials indicate that the MEK inhibitor (MEKi) trametinib may be a good treatment option for a subset of patients. Understanding MEKi-resistance mechanisms and subsequent identification of rational drug combinations to suppress resistance may greatly improve LGSOC treatment strategies.

EGFR activation limits the response of liver cancer to lenvatinib.

Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer.

ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors.

Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines.

Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma.

Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor and activating mutations in the PI3K subunit In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models. In a large set of patients with OCCC ( = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined.

Loss of ARID1A Activates ANXA1, which Serves as a Predictive Biomarker for Trastuzumab Resistance.

Purpose: Despite the substantial progress in the development of targeted anticancer drugs, treatment failure due to primary or acquired resistance is still a major hurdle in the effective treatment of most advanced human cancers. Understanding these resistance mechanisms will be instrumental to improve personalized cancer treatment.

Experimental Design: Genome-wide loss-of-function genetic screens were performed to identify genes implicated in resistance to HER2/PI3K/mTOR targeting agents in HER2 breast cancer cell lines.

USP9X downregulation renders breast cancer cells resistant to tamoxifen.

Tamoxifen is one of the most widely used endocrine agents for the treatment of estrogen receptor α (ERα)-positive breast cancer. Although effective in most patients, resistance to tamoxifen is a clinically significant problem and the mechanisms responsible remain elusive. To address this problem, we performed a large scale loss-of-function genetic screen in ZR-75-1 luminal breast cancer cells to identify candidate resistance genes.

Existential crisis and the awareness of dying: the role of meaning and spirituality.

An existential crisis may occur in cancer patients when they realize that their death may be imminent. We explore the ways in which patients deal with this crisis, in which the meaning of life itself is at stake. In dealing with an existential crisis, it is important to have the courage to confront the loss of meaning and security.

A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer.

A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone.

A functional genetic screen identifies TFE3 as a gene that confers resistance to the anti-proliferative effects of the retinoblastoma protein and transforming growth factor-beta.

The helix-loop-helix transcription factor TFE3 has been suggested to play a role in the control of cell growth by acting as a binding partner of transcriptional regulators such as E2F3, SMAD3, and LEF-1. Furthermore, translocations/TFE3 fusions have been directly implicated in tumorigenesis. Surprisingly, however, a direct functional role for TFE3 in the regulation of proliferation has not been reported.

A functionally distinct member of the DP family of E2F subunits.

E2F transcription factors regulate genes involved in cell-cycle progression. In mammalian cells, physiological E2F exists as an E2F/DP heterodimer. Currently, eight E2F and two DP subunits have been characterized.

PR72, a novel regulator of Wnt signaling required for Naked cuticle function.

The Wnt signaling cascade is a central regulator of cell fate determination during embryonic development, whose deregulation contributes to oncogenesis. Naked cuticle is the first Wnt-induced antagonist found in this pathway, establishing a negative-feedback loop that limits the Wnt signal required for early segmentation. In addition, Naked cuticle is proposed to function as a switch, acting to restrict classical Wnt signaling and to activate a second Wnt signaling pathway that controls planar cell polarity during gastrulation movements in vertebrates.

E2F-7: a distinctive E2F family member with an unusual organization of DNA-binding domains.

The E2F family of transcription factors play an important role in regulating cell cycle progression. We report here the characterization and functional properties of a new member of the human E2F family, referred to as E2F-7. E2F-7 has two separate DNA-binding domains, a feature that distinguishes E2F-7 from other mammalian E2F proteins, but resembling the organization of recently isolated E2F-like proteins from Arabidopsis.

A large-scale RNAi screen in human cells identifies new components of the p53 pathway.

RNA interference (RNAi) is a powerful new tool with which to perform loss-of-function genetic screens in lower organisms and can greatly facilitate the identification of components of cellular signalling pathways. In mammalian cells, such screens have been hampered by a lack of suitable tools that can be used on a large scale. We and others have recently developed expression vectors to direct the synthesis of short hairpin RNAs (shRNAs) that act as short interfering RNA (siRNA)-like molecules to stably suppress gene expression.

A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts.

The c-myc gene is frequently over-expressed in human cancers and is involved in regulation of proliferation, differentiation and apoptosis. c-Myc is a transcription factor that acts primarily by regulating the expression of other genes. However, it has been very difficult to identify bona fide c-Myc target genes that explain its diverse biological activities.

Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastoma-related p107 protein.

The proteins of the retinoblastoma family are potent inhibitors of cell cycle progression. It is well documented that their growth-inhibitory activity can be abolished by phosphorylation on serine and threonine residues by cyclin dependent kinases. In contrast, very little is known about the dephosphorylation of retinoblastoma-family proteins.

Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1.

The estrogen receptor (ER) is an important regulator of growth and differentiation of breast epithelium. Transactivation by ER depends on a leucine-rich motif, which constitutes a ligand-regulated binding site for steroid receptor coactivators (SRCs). Cyclin D1 is frequently amplified in breast cancer and can activate ER through direct binding.

Repression of c-Myc responsive genes in cycling cells causes G1 arrest through reduction of cyclin E/CDK2 kinase activity.

The c-myc gene encodes a sequence-specific DNA binding protein involved in proliferation and oncogenesis. Activation of c-myc expression in quiescent cells is sufficient to mediate cell cycle entry, whereas inhibition of c-myc expression causes cycling cells to withdraw from the cell cycle. To search for components of the cell cycle machinery that are targets of c-Myc, we have made a mutant c-Myc protein, named MadMyc, that actively represses c-myc target genes.

mUBC9, a novel adenovirus E1A-interacting protein that complements a yeast cell cycle defect.

Adenovirus E1A encodes two nuclear phosphoproteins that can transform primary rodent fibroblasts in culture. Transformation by E1A is mediated at least in part through binding to several cellular proteins, including the three members of the retinoblastoma family of growth inhibitory proteins. We report here the cloning of a novel murine cDNA whose encoded protein interacts with both adenovirus type 5 and type 12 E1A proteins.

Functional analysis of Burkitt's lymphoma mutant c-Myc proteins.

The c-myc gene encodes a sequence-specific DNA binding protein that activates transcription of cellular genes. Transcription activation by Myc proteins is regulated by phosphorylation of serine and threonine residues within the transactivation domain and by complex formation with the retinoblastoma-related protein p107. In Burkitt's lymphoma, missense mutations within the c-Myc transactivation domain have been found with high frequency.

Molecular and functional characterisation of E2F-5, a new member of the E2F family.

The transcription factor DRTF1/E2F is implicated in the control of cellular proliferation due to its interaction with key regulators of cell cycle progression, such as the retinoblastoma tumour suppressor gene product and related pocket proteins, cyclins and cyclin-dependent kinases. DRTF1/E2F DNA binding activity arises when a member of two distinct families of proteins, DP and E2F, interact as DP/E2F heterodimers. Here, we report the isolation and characterisation of a new member of the E2F family of proteins, called E2F-5.

E2F-5, a new E2F family member that interacts with p130 in vivo.

E2F DNA binding sites are found in a number of genes whose expression is tightly regulated during the cell cycle. The activity of E2F transcription factors is regulated by association with specific repressor molecules that can bind and inhibit the E2F transactivation domain. For E2F-1, E2F-2, and E2F-3, the repressor is the product of the retinoblastoma gene, pRb.

Interaction of c-Myc with the pRb-related protein p107 results in inhibition of c-Myc-mediated transactivation.

The product of the c-myc proto-oncogene, c-Myc, is a sequence-specific DNA binding protein with an N-terminal transactivation domain and a C-terminal DNA binding domain. Several lines of evidence indicate that c-Myc activity is essential for normal cell cycle progression. Since the abundance of c-Myc during the cell cycle is constant, c-Myc's activity may be regulated at a post-translational level.