Abstract PR11: Characterizing the mechanism and the clinical relevance of the synthetic lethal interaction between STAT3 inhibition and HER2 overexpression in breast cancers

ABSTRACT Combinatorial chemotherapy is necessary for the treatment of malaria. However, finding a suitable partner drug for a new candidate is challenging. Here we develop an algorithm that identifies all of the gene pairs of Plasmodium falciparum that possess orthologues in yeast that have a synthetic lethal interaction but are absent in humans. This suggests new options for drug combinations, particularly for inhibitors of targets such as P. falciparum calcineurin, cation ATPase 4, or phosphatidylinositol 4-kinase.

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Current Approaches and Emerging Directions in HER2-resistant Breast Cancer

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s9453 ◽

2014 ◽

Vol 8 ◽

pp. BCBCR.S9453 ◽

Cited By ~ 6

Author(s):

Adam M. Brufsky

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Molecular Mechanisms ◽

Mammalian Target Of Rapamycin ◽

Growth Factor Receptor ◽

Initial Response ◽

Her2 Overexpression ◽

Breast Cancers ◽

Intrinsic Resistance ◽

Her2 Positive

Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancers; HER2 overexpression is indicative of poor prognosis. Trastuzumab, an anti-HER2 monoclonal antibody, has led to improved outcomes in patients with HER2-positive breast cancer, including improved overall survival in adjuvant and first-line settings. However, a large proportion of patients with breast cancer have intrinsic resistance to HER2-targeted therapies, and nearly all become resistant to therapy after initial response. Elucidation of underlying mechanisms contributing to HER2 resistance has led to development of novel therapeutic strategies, including those targeting HER2 and downstream pathways, heat shock protein 90, telomerase, and vascular endothelial growth factor inhibitors. Numerous clinical trials are ongoing or completed, including phase 3 data for the mammalian target of rapamycin inhibitor everolimus in patients with HER2-resistant breast cancer. This review considers the molecular mechanisms associated with HER2 resistance and evaluates the evidence for use of evolving strategies in patients with HER2-resistant breast cancer.

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Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers13164139 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4139

Author(s):

Pere Llinàs-Arias ◽

Sandra Íñiguez-Muñoz ◽

Kelly McCann ◽

Leonie Voorwerk ◽

Javier I. J. Orozco ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Immune Escape ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Regulatory Elements ◽

Her2 Overexpression ◽

Breast Cancers ◽

Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

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Histopathology findings of non-mass cancers on breast ultrasound

Acta Radiologica Open ◽

10.1177/2058460118774957 ◽

2018 ◽

Vol 7 (6) ◽

pp. 205846011877495 ◽

Cited By ~ 1

Author(s):

Hye Rin Kim ◽

Hae Kyoung Jung

Keyword(s):

Ductal Carcinoma ◽

Immunohistochemical Analysis ◽

Breast Ultrasound ◽

Her2 Overexpression ◽

Tumor Type ◽

Breast Cancers ◽

Mammographic Finding ◽

Minimal Invasion ◽

Mass Lesions

Background There is little research done on non-mass cancers (NMCs) on breast ultrasound (US). Purpose To evaluate large-sectional histopathology findings of NMCs on breast US. Material and Methods The mammographic and histopathology features of biopsy proven 36 breast cancers which showed pure non-mass lesions on US were retrospectively reviewed. Results The most common mammographic finding was microcalcification (23/35, 65.7%); fine pleomorphic microcalcification was predominant (18/23, 78.3%). The main tumor type was pure ductal carcinoma in situ (DCIS) (14/36, 38.9%) and DCIS with micro- or minimal invasion (11/36, 30.6%). Among the 25 DCIS, histologic grade was high in 15 (60.0%) and intermediate in nine (36%); comedo necrosis was seen in 17 (68%). Immunohistochemical analysis was available in 27 lesions and showed HER2-overexpression in 12 (44.4%) and triple-negative in two (7.4%). Conclusion According to our limited patient sample, NMCs on breast US were mainly associated with high-grade DCIS.

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BTK inhibition sensitizes Acute Lymphoblastic Leukemia to asparaginase by suppressing the Amino Acid Response pathway

Blood ◽

10.1182/blood.2021011787 ◽

2021 ◽

Author(s):

Miriam Butler ◽

Dorette S van Ingen Schenau ◽

Jiangyan Yu ◽

Silvia Jenni ◽

Maria Pamela Dobay ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Amino Acid ◽

Tyrosine Kinase ◽

Lymphoblastic Leukemia ◽

Synthetic Lethal Interaction ◽

Synthetic Lethal ◽

Genetic Inactivation ◽

Pdx Model ◽

Btk Inhibitor ◽

Amino Acid Response

Asparaginase (ASNase) therapy has been a mainstay of Acute Lymphoblastic Leukemia (ALL) protocols for decades and shows promise in the treatment of a variety of other cancers. To improve the efficacy of ASNase treatment, we employed a CRISPR/Cas9-based screen to identify actionable signaling intermediates that improve the response to ASNase. Both genetic inactivation of Bruton's Tyrosine Kinase (BTK) and pharmacological inhibition by the BTK inhibitor ibrutinib strongly synergize with ASNase by inhibiting the amino acid response pathway, a mechanism involving c-Myc mediated suppression of GCN2 activity. This synthetic lethal interaction was observed in 90% of patient derived xenografts, irrespective of the genomic subtype. Moreover, ibrutinib substantially improved ASNase treatment response in a murine PDX model. Hence, ibrutinib may be used to enhance the clinical efficacy of ASNase in ALL.

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Synthetic Lethal Interaction between the ESCRT Paralog Enzymes VPS4A and VPS4B in Cancers Harboring Loss of Chromosome 18q or 16q

Cell Reports ◽

10.1016/j.celrep.2020.108493 ◽

2020 ◽

Vol 33 (11) ◽

pp. 108493 ◽

Cited By ~ 1

Author(s):

Jasper E. Neggers ◽

Brenton R. Paolella ◽

Adhana Asfaw ◽

Michael V. Rothberg ◽

Thomas A. Skipper ◽

...

Keyword(s):

Synthetic Lethal Interaction ◽

Synthetic Lethal ◽

Chromosome 18Q

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SL-BioDP: Multi-Cancer Interactive Tool for Prediction of Synthetic Lethality and Response to Cancer Treatment

Cancers ◽

10.3390/cancers11111682 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1682 ◽

Cited By ~ 4

Author(s):

Xiang Deng ◽

Shaoli Das ◽

Kristin Valdez ◽

Kevin Camphausen ◽

Uma Shankavaram

Keyword(s):

Clinical Relevance ◽

Synthetic Lethality ◽

Drug Efficacy ◽

Synthetic Lethal ◽

Cancer Data ◽

Cancer Pathways ◽

Kaplan Meier ◽

Survival Pathways ◽

Synthetic Lethal Interactions ◽

Cancer Genome Atlas

Synthetic lethality exploits the phenomenon that a mutation in a cancer gene is often associated with new vulnerability which can be uniquely targeted therapeutically, leading to a significant increase in favorable outcome. DNA damage and survival pathways are among the most commonly mutated networks in human cancers. Recent data suggest that synthetic lethal interactions between a tumor defect and a DNA repair pathway can be used to preferentially kill tumor cells. We recently published a method, DiscoverSL, using multi-omic cancer data, that can predict synthetic lethal interactions of potential clinical relevance. Here, we apply the generality of our models in a comprehensive web tool called Synthetic Lethality Bio Discovery Portal (SL-BioDP) and extend the cancer types to 18 cancer genome atlas cohorts. SL-BioDP enables a data-driven computational approach to predict synthetic lethal interactions from hallmark cancer pathways by mining cancer’s genomic and chemical interactions. Our tool provides queries and visualizations for exploring potentially targetable synthetic lethal interactions, shows Kaplan–Meier plots of clinical relevance, and provides in silico validation using short hairpin RNA (shRNA) and drug efficacy data. Our method would thus shed light on mechanisms of synthetic lethal interactions and lead to the discovery of novel anticancer drugs.

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