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Neil Johnson, PhD

Neil Johnson, PhD
About

Assistant Professor

Research Program

Education, Training & Credentials

Educational Background

  • BSc, Genetics and Biochemistry, Newcastle University, Newcastle upon Tyne, UK, 2002
  • PhD, Cancer Biology and Therapeutics, Newcastle University, Newcastle upon Tyne, UK, 2006

Honors & Awards

  • DFCI/HCC Breast SPORE Career Development Award , 2010
  • AACR-Aflac Scholar-in-Training Award, 2011
  • Claudia-Adams Barr Program in Innovative Cancer Research Award, Dana-Farber Cancer Institute, 2012
  • Susan G. Komen Career Catalyst, 2013
  • FCCC-UPEN Ovarian SPORE Career Development Award, Fox Chase Cancer Center, 2013
  • External Research Grant Award, Basser Center for BRCA Research, 2014
  • Ovarian Cancer Academy Award, Department of Defense, 2014
Research Profile

Research Program

Research Interests

BRCA biology and therapy resistance

  • Study and characterization of mRNA and protein products generated from germline BRCA mutant alleles.
  • The role of mutant BRCA proteins in the DNA damage response.
  • Mechanisms of resistance to PARP inhibitor and platinum therapy.

Lab Overview

The BRCA1 gene is commonly mutated in hereditary breast and ovarian cancers. Mutations occur most frequently in the N-terminal RING, exons 11-13, or the BRCA C-terminal (BRCT) domain. The BRCA1 protein has multiple domains that mediate protein interactions; BRCA1 gene mutations may produce truncated proteins that lose the ability to interact with associated proteins. Additionally, mutations in the BRCT domain of BRCA1 create protein-folding defects that result in protease-mediated degradation.  Cells that contain dysfunctional BRCA1 proteins are hypersensitive to DNA damaging agents. In particular, BRCA1-deficient cell lines are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitor treatment.  Despite substantial response rates of BRCA1 mutant cancers to PARP inhibitor treatment, many patients harboring BRCA1 mutant tumors fail to respond to treatment; additionally, patients that demonstrate initial responses ultimately acquire drug resistant tumors.

Our research involves investigating factors that enable cancer cells containing BRCA mutations to carry out homologous recombination DNA repair and survive DNA damaging agent chemotherapy. Several factors may contribute to homologous recombination DNA repair proficiency in BRCA mutant tumors. We are examining the ability of mutant BRCA1 proteins to contribute to homologous recombination in cancer cells. Additionally, in collaboration with the Broad Institute at MIT/Harvard, we have screened a genome scale open reading frame (ORF) library to identify proteins that provide PARP inhibitor resistance. Furthermore, we are measuring the ability of novel or established compounds in preclinical or clinical development to abrogate DNA repair pathways. Our overarching goal is to exploit discoveries in basic science for therapeutic benefit and translation to clinical trials.

People

Andrea Bernhardy, BA

Technical Specialist

Room: W446
215-728-7015

Yifan Wang, PhD

Postdoctoral Associate

Room: W446
215-728-7086

John Krais, PhD, BS

Postdoctoral Associate

Room: W446
215-728-7077

Joseph Nacson, MD

Graduate Student

Room: W446
215-278-3604
Publications

Selected Publications

Johnson N, Speirs V, Curtin NJ and Hall AG. A comparative study of genome-wide SNP, CGH microarray and protein expression analysis to explore genotypic and phenotypic mechanisms of acquired antiestrogen resistance in breast cancer. Breast Cancer Res Treat 2008 Sep;111(1):55-63. PubMed

Johnson N, Cai D, Kennedy RD, Pathania S, Arora M, Li YC, D’Andrea AD, Parvin J.D and Shapiro GI. CDK1 participates in BRCA1-dependent S phase checkpont control in response to DNA damage.  Molecular Cell 2009 Aug 14;35(3):327-39. PubMed

 Johnson N, Bentley J, Wang LZ, Newell DR, Robson CN, Shapiro GI, Curtin NJ. Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen sensitive and resistant breast cancer cells. Br J Cancer  2010 Jan 19;102(2):342-50. PubMed

  Johnson N and Shapiro GI. Targeting cyclin-dependent kinases for cancer therapy. Cell cycle deregulation in cancer; GH Enders (ed.) 2010.

Johnson N, Shapiro GI. Cyclin-dependent kinases (CDKs) and the DNA damage response: rationale for CDK inhibitor-chemotherapy combinations as an anticancer strategy for solid tumors. Expert Opin Ther Targets. 2010 Nov; 14(11):1199-212. PubMed

Johnson N, Li Y-C, Walton ZE, Cheng KA, Li D, Rodig SJ, Moreau LA, Unitt C, Bronson RT, Thomas HD, Newell DR, D’Andrea AD, Curtin NJ, Wong KK, Shapiro GI.  Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition.  Nature Medicine 2011 Jun 26;17(7):875-82. PubMed

Johnson N, Shapiro GI. Chemotherapy-induced p53-dependent and -independent DNA damage responses are enhanced by poly(ADP-ribose) polymerase (PARP) inhibition in BRCA-proficient cancer cells. Cell Cycle. 2012 Feb 1;11(3). PubMed

 Johnson N, Shapiro GI. Cyclin-dependent kinase 4/6 inhibition in cancer therapy. Cell Cycle. 2012 Nov 1;11(21):3913. PubMed

Johnson N, Johnson SF, Yao W, Bernhardy AJ, Wang Y, Li Y-L, Choi Y-E, Capelletti M, Sarosiek KA, Moreau LA, Chowdhury D, Wickramanayake A, Harrell M, Liu JF, D’Andrea AD, Miron A, Swisher EM, Shapiro GI. Stabilization of mutant BRCA1 confers PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):17041-6. PubMed