Publications by authors named "Pingping Mao"

5 Publications

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Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER Metastatic Breast Cancer.

Clin Cancer Res 2020 Nov 28;26(22):5974-5989. Epub 2020 Jul 28.

Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: To identify clinically relevant mechanisms of resistance to ER-directed therapies in ER breast cancer.

Experimental Design: We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. In parallel, we performed whole-exome sequencing in paired pretreatment and postresistance biopsies from 60 patients with ER metastatic breast cancer who had developed resistance to ER-targeted therapy. Furthermore, we performed experiments to validate resistance genes/pathways and to identify drug combinations to overcome resistance.

Results: Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. The FGFR pathway was altered via , or amplifications or mutations in 24 (40%) of the postresistance biopsies. In 12 of the 24 postresistance tumors exhibiting FGFR/FGF alterations, these alterations were acquired or enriched under the selective pressure of ER-directed therapy. experiments in ER breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib. RNA sequencing of resistant cell lines demonstrated that FGFR/FGF induced resistance through ER reprogramming and activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors, a MEK inhibitor, and/or a SHP2 inhibitor.

Conclusions: Our results suggest that FGFR pathway is a distinct mechanism of acquired resistance to ER-directed therapy that can be overcome by FGFR and/or MAPK pathway inhibitors.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3958DOI Listing
November 2020

The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor-Positive Metastatic Breast Cancer.

Cancer Discov 2020 Aug 13;10(8):1174-1193. Epub 2020 May 13.

Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including loss, activating alterations in , and , and loss of estrogen receptor expression. experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired , or alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in , and -have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients. SIGNIFICANCE: We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR metastatic breast cancer..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1390DOI Listing
August 2020

Headway and hurdles in the clinical development of dietary phytochemicals for cancer therapy and prevention: lessons learned from vitamin A derivatives.

AAPS J 2014 Mar 16;16(2):281-8. Epub 2014 Jan 16.

Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, 7650 Remsen, Hanover, New Hampshire, 03755, USA.

Accumulating epidemiologic and preclinical evidence support the pharmacologic use of a variety of dietary chemicals for the prevention and treatment of cancer. However, it will be challenging to translate these findings into routine clinical practice since phytochemicals have pleiotropic biological activities that have to be balanced for optimal efficacy without unacceptable and potentially unanticipated toxicities. Correctly matching patient populations and settings with optimal, natural product-based phytochemical therapies will require a greater understanding of the specific mechanisms underlying the efficacy, toxicity, and resistance of each agent in a variety of normal, premalignant, and malignant settings. This, in turn, necessitates continued commitment from the basic research community to guide carefully designed and informed clinical trials. The most developed class of anticancer phytochemicals consists of the derivatives of vitamin A called retinoids. Unlike other natural product chemicals currently under study, the retinoids have been extensively tested in humans. Over 30 years of clinical investigation has resulted in several disappointments, but there were some spectacular successes where certain retinoid-based protocols are now FDA-approved standard of care therapies to treat specific malignancies. Furthermore, retinoids are one of the most evaluated pharmacologic agents in the ultra-challenging setting of interventional cancer prevention. This review will summarize the development of retinoids in cancer therapy and prevention with an emphasis on currently proposed mechanisms mediating their efficacy, toxicity, and resistance.
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http://dx.doi.org/10.1208/s12248-014-9562-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933572PMC
March 2014

Serine/threonine kinase 17A is a novel candidate for therapeutic targeting in glioblastoma.

PLoS One 2013 28;8(11):e81803. Epub 2013 Nov 28.

Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

STK17A is a relatively uncharacterized member of the death-associated protein family of serine/threonine kinases which have previously been associated with cell death and apoptosis. Our prior work established that STK17A is a novel p53 target gene that is induced by a variety of DNA damaging agents in a p53-dependent manner. In this study we have uncovered an additional, unanticipated role for STK17A as a candidate promoter of cell proliferation and survival in glioblastoma (GBM). Unexpectedly, it was found that STK17A is highly overexpressed in a grade-dependent manner in gliomas compared to normal brain and other cancer cell types with the highest level of expression in GBM. Knockdown of STK17A in GBM cells results in a dramatic alteration in cell shape that is associated with decreased proliferation, clonogenicity, migration, invasion and anchorage independent colony formation. STK17A knockdown also sensitizes GBM cells to genotoxic stress. STK17A overexpression is associated with a significant survival disadvantage among patients with glioma which is independent of age, molecular phenotype, IDH1 mutation, PTEN loss, and alterations in the p53 pathway and partially independent of grade. In summary, we demonstrate that STK17A provides a proliferative and survival advantage to GBM cells and is a potential target to be exploited therapeutically in patients with glioma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081803PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842963PMC
December 2014

Serine/threonine kinase 17A is a novel p53 target gene and modulator of cisplatin toxicity and reactive oxygen species in testicular cancer cells.

J Biol Chem 2011 Jun 13;286(22):19381-91. Epub 2011 Apr 13.

Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.

Testicular cancer is highly curable with cisplatin-based therapy, and testicular cancer-derived human embryonal carcinoma (EC) cells undergo a p53-dominant transcriptional response to cisplatin. In this study, we have discovered that a poorly characterized member of the death-associated protein family of serine/threonine kinases, STK17A (also called DRAK1), is a novel p53 target gene. Cisplatin-mediated induction of STK17A in the EC cell line NT2/D1 was prevented with p53 siRNA. Furthermore, STK17A was induced with cisplatin in HCT116 and MCF10A cells but to a much lesser extent in isogenic p53-suppressed cells. A functional p53 response element that binds endogenous p53 in a cisplatin-dependent manner was identified 5 kb upstream of the first coding exon of STK17A. STK17A is not present in the mouse genome, but the closely related gene STK17B is induced with cisplatin in mouse NIH3T3 cells, although this induction is p53-independent. Interestingly, in human cells containing both STK17A and STK17B, only STK17A is induced with cisplatin. Knockdown of STK17A conferred resistance to cisplatin-induced growth suppression and apoptotic cell death in EC cells. This was associated with the up-regulation of detoxifying and antioxidant genes, including metallothioneins MT1H, MT1M, and MT1X that have previously been implicated in cisplatin resistance. In addition, knockdown of STK17A resulted in decreased cellular reactive oxygen species, whereas STK17A overexpression increased reactive oxygen species. In summary, we have identified STK17A as a novel direct target of p53 and a modulator of cisplatin toxicity and reactive oxygen species in testicular cancer cells.
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http://dx.doi.org/10.1074/jbc.M111.218040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103316PMC
June 2011