Associate Professor
BRCA biology and therapy resistance
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.
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
neil.johnson@fccc.edu
Office Phone: 215-728-7016
Fax: 215-728-3616
Office: P3139
neil.johnson@fccc.edu
Office Phone: 215-728-7016
Fax: 215-728-3616
Office: P3139
Associate Professor
BRCA biology and therapy resistance
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.
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
This Fox Chase professor participates in the Undergraduate Summer Research Fellowship.
Learn more about Research Volunteering.
