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Neil Johnson, PhD

Neil Johnson, PhD
Education and Training

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.
  • The role of BRCA proteins in DNA replication.
  • 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 both cancer cell line models and genetically engineered mouse models. 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.

Lab Staff

Andrea Bernhardy, BA

Technical Specialist

Room: P3101
215-728-7015

Gregory Conway, PhD, MA

Postdoctoral Associate

Room: P3101
215-728-7133

Erica Huelsmann, MD

Rotating Gynecologic Oncology Fellow

Room: P3101
215-728-7077

John Krais, PhD, BS

Postdoctoral Associate

Room: P3101
215-728-7077

Yifan Wang, PhD

Research Associate

Room: P3101
215-728-7086

Darlene Curran

Administrative Assistant

Room: P3048
215-214-1643

Additional Staff

Former Lab Members

Emma Clausen, BA
Scientific Technician I
Room: P3101 | 215-278-7020 | emma.clausen@fccc.edu

Joseph Nacson, MD
Graduate Student
Room: P3101 | 215-728-3604 | joseph.nacson@fccc.edu

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

Wang Y, Bernhardy AJ, Cruz C, Krais JJ, Nacson J, Nicolas E, Peri S, van der Gulden H, van der Heijden I, O'Brien SW, Zhang Y, Harrell MI, Johnson SF, Candido Dos Reis FJ, Pharoah PD, Karlan B, Gourley C, Lambrechts D, Chenevix-Trench G, Olsson H, Benitez JJ, Greene MH, Gore M, Nussbaum R, Sadetzki S, Gayther SA, Kjaer SK; kConFab Investigators, D'Andrea AD, Shapiro GI, Wiest DL, Connolly DC, Daly MB, Swisher EM, Bouwman P, Jonkers J, Balmaña J, Serra V, Johnson N. The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. Cancer Res. 2016 May 1;76(9):2778-90. doi: 10.1158/0008-5472.CAN-16-0186 PubMed

Wang Y, Krais JJ, Bernhardy AJ, Nicolas E, Cai KQ, Harrell MI, Kim HH, George E, Swisher EM, Simpkins F, Johnson N. BRCA1 RING Domain-Deficient Proteins Promote PARP Inhibitor and Platinum Resistance. J Clin Invest. 2016 Aug 1;126(8):3145-57. PubMed 

Villamar Cruz O, Prudnikova TY, Araiza-Olivera D, Perez-Plasencia C, Johnson N, Bernhardy AJ, Slifker M, Renner C, Chernoff J, Arias-Romero LE. Reduced PAK1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition. Oncotarget. 2016 Nov 22;7(47):76590-76603. doi: 10.18632/oncotarget.12576.  PubMed

Johnson SF, Cruz C, Greifenberg AK, Dust S, Stover DG,  Chi D, Primack B, Cao S, Bernhardy AJ, Coulson R, Lazaro JB, Kochupurakkal B, Sun H, Unitt C, Moreau LA, Sarosiek KA, Scaltriti M, Juric D, Baselga J, Richardson AL, Rodig SJ, D'Andrea AD, Balmaña J, Johnson N, Geyer M, Serra V, Lim E, Shapiro GI. CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer.  Cell reports. 2016; 17(9):2367-2381. PubMed

George E, Kim H, Krepler C, Wenz B, Makvandi M, Tanyi JL, Brown E, Zhang R, Brafford P, Jean S, Mach RH, Lu Y, Mills GB, Herlyn M, Morgan M, Zhang X, Soslow R, Drapkin R, Johnson N, Zheng Y, Cotsarelis G, Nathanson KL, Simpkins F. A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers. JCI Insight. 2017 Jan 12;2(1):e89760. doi: 10.1172/jci.insight.89760. PubMed PMID: 28097235; PubMed Central PMCID: PMC5214535. PubMed

Johnson N, Liao JB. Novel Therapeutics for Ovarian Cancer: The 11th Biennial Rivkin Center Ovarian Cancer Research Symposium. Int J Gynecol Cancer. 2017 Nov;27(9S Suppl 5):S14-S19. doi: 10.1097/IGC.0000000000001115. PubMed PMID: 29040190. PubMed

Sullivan-Reed K, Bolton-Gillespie E, Dasgupta Y, Langer S, Siciliano M, Nieborowska-Skorska M, Hanamshet K, Belyaeva EA, Bernhardy AJ, Lee J, Moore M, Zhao H, Valent P, Matlawska-Wasowska K, Müschen M, Bhatia S, Bhatia R, Johnson N, Wasik MA, Mazin AV, Skorski T. Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells. Cell Rep. 2018 Jun 12;23(11):3127-3136. doi: 10.1016/j.celrep.2018.05.034. PubMed PMID: 29898385; PubMed Central PMCID: PMC6082171. PubMed

Nacson J, Krais JJ, Bernhardy AJ, Clausen E, Feng W, Wang Y, Nicolas E, Cai KQ, Tricarico R, Hua X, DiMarcantonio D, Martinez E, Zong D, Handorf EA, Bellacosa A, Testa JR, Nussenzweig A, Gupta GP, Sykes SM, Johnson N. BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance. Cell Rep. 2018 Sep 25;24(13):3513-3527.e7. doi: 10.1016/j.celrep.2018.08.086. PubMed PMID: 30257212; PubMed Central PMCID: PMC6219632. PubMed

Kondrashova O, Topp M, Nesic K, Lieschke E, Ho GY, Harrell MI, Zapparoli GV, Hadley A, Holian R, Boehm E, Heong V, Sanij E, Pearson RB, Krais JJ, Johnson N, McNally O, Ananda S, Alsop K, Hutt KJ, Kaufmann SH, Lin KK, Harding TC, Traficante N, deFazio A, McNeish IA, Bowtell DD, Swisher EM, Dobrovic A, Wakefield MJ, Scott CL. Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. Nat Commun. 2018 Sep 28;9(1):3970. doi: 10.1038/s41467-018-05564-z. PubMed PMID: 30266954; PubMed Central PMCID: PMC6162272. PubMed

Nacson J, Krais JJ, Bernhardy AJ, Clausen E, Feng W, Wang Y, Nicolas E, Cai KQ, Tricarico R, Hua X, DiMarcantonio D, Martinez E, Zong D, Handorf EA, Bellacosa A, Testa JR, Nussenzweig A, Gupta GP, Sykes SM, Johnson N. BRCA1 Mutation-Specific Responses to 53BP1 Loss-Induced Homologous Recombination and PARP Inhibitor Resistance. Cell Rep. 2018 Oct 30;25(5):1384. doi: 10.1016/j.celrep.2018.10.009. PubMed PMID: 30380426; PubMed Central PMCID: PMC6296467. PubMed

Zong D, Adam S, Wang Y, Sasanuma H, Callén E, Murga M, Day A, Kruhlak MJ, Wong N, Munro M, Ray Chaudhuri A, Karim B, Xia B, Takeda S, Johnson N, Durocher D, Nussenzweig A. BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation. Mol Cell. 2019 Mar 21;73(6):1267-1281.e7. doi: 10.1016/j.molcel.2018.12.010. Epub 2019 Jan 28. PubMed PMID: 30704900; PubMed Central PMCID: PMC6430682. PubMed

Gabbasov R, Benrubi ID, O'Brien SW, Krais JJ, Johnson N, Litwin S, Connolly DC. Targeted blockade of HSP90 impairs DNA-damage response proteins and increases the sensitivity of ovarian carcinoma cells to PARP inhibition. Cancer Biol Ther. 2019;20(7):1035-1045. doi: 10.1080/15384047.2019.1595279. Epub 2019 Mar 30. PubMed PMID: 30929564; PubMed Central PMCID: PMC6606007. PubMed

Wang Y, Bernhardy AJ, Nacson J, Krais JJ, Tan YF, Nicolas E, Radke MR, Handorf E, Llop-Guevara A, Balmaña J, Swisher EM, Serra V, Peri S, Johnson N. BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance. Nat Commun. 2019 Dec 11;10(1):5661. doi: 10.1038/s41467-019-13530-6. PubMed PMID: 31827092; PubMed Central PMCID: PMC6906494. PubMed

Park PH, Yamamoto TM, Li H, Alcivar AL, Xia B, Wang Y, Bernhardy AJ, Turner KM, Kossenkov AV, Watson ZL, Behbakht K, Casadei S, Swisher EM, Mischel PS, Johnson N, Bitler BG. Amplification of the Mutation-Carrying BRCA2 Allele Promotes RAD51 Loading and PARP Inhibitor Resistance in the Absence of Reversion Mutations. Mol. Cancer Ther. 2020 Feb;19(2):602-613. doi: 10.1158/1535-7163.MCT-17-0256. Epub 2019 Oct 1. PubMed PMID: 31575654; PubMed Central PMCID: PMC7007853. PubMed

Krais JJ, Johnson N. Ectopic RNF168 expression promotes break-induced replication-like DNA synthesis at stalled replication forks. Nucleic Acids Res. 2020 May 7;48(8):4298-4308. doi: 10.1093/nar/gkaa154. PubMed PMID: 32182354; PubMed Central PMCID: PMC7192614. PubMed

Nacson J, Di Marcantonio D, Wang Y, Bernhardy AJ, Clausen E, Hua X, Cai KQ, Martinez E, Feng W, Callén E, Wu W, Gupta GP, Testa JR, Nussenzweig A, Sykes SM, Johnson N. BRCA1 Mutational Complementation Induces Synthetic Viability. Mol Cell. 2020 Jun 4;78(5):951-959.e6. doi: 10.1016/j.molcel.2020.04.006. Epub 2020 Apr 30. PubMed PMID: 32359443; PubMed Central PMCID: PMC7418109. PubMed

Krais JJ, Wang Y, Bernhardy AJ, Clausen E, Miller JA, Cai KQ, Scott CL, Johnson N. RNF168-Mediated Ubiquitin Signaling Inhibits the Viability of BRCA1-Null Cancers. Cancer Res. 2020 Jul 1;80(13):2848-2860. doi: 10.1158/0008-5472.CAN-19-3033. Epub 2020 Mar 25. PubMed PMID: 32213544; PubMed Central PMCID: PMC7335334. PubMed

Krais JJ, Johnson N. Brca1 mutations in the coiled-coil domain impede Rad51 loading on DNA and mouse development. Mol Cell Oncol. 2020;7(5):1786345. doi: 10.1080/23723556.2020.1786345. eCollection 2020. PubMed PMID: 32944641; PubMed Central PMCID: PMC7469674. PubMed

Kim H, Xu H, George E, Hallberg D, Kumar S, Jagannathan V, Medvedev S, Kinose Y, Devins K, Verma P, Ly K, Wang Y, Greenberg RA, Schwartz L, Johnson N, Scharpf RB, Mills GB, Zhang R, Velculescu VE, Brown EJ, Simpkins F. Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun. 2020 Jul 24;11(1):3726. doi: 10.1038/s41467-020-17127-2. PubMed PMID: 32709856; PubMed Central PMCID: PMC7381609. PubMed

Krais JJ, Johnson N. BRCA1 Mutations in Cancer: Coordinating Deficiencies in Homologous Recombination with Tumorigenesis. Cancer Res. 2020 Aug 3;. doi: 10.1158/0008-5472.CAN-20-1830. [Epub ahead of print] Review. PubMed PMID: 32747362; NIHMSID:NIHMS1617898. PubMed

Additional Publications

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