Background: Prostate cancer is one of the most prevalent cancers in males in the United States and amongst the leading causes of cancer related deaths. A particularly virulent form of this disease is castration-resistant prostate cancer (CRPC), where patients no longer respond to medical or surgical castration. CRPC is a complex, multifaceted and heterogeneous malady with limited standard treatment options.Results: The growth and progression of prostate cancer is a complicated process that involves multiple pathways. The signaling network comprising the integral constituents of the signature pathways involved in the development and progression of prostate cancer is modeled as a combinatorial circuit. The failures in the gene regulatory network that lead to cancer are abstracted as faults in the equivalent circuit and the Boolean circuit model is then used to design therapies tailored to counteract the effect of each molecular abnormality and to propose potentially efficacious combinatorial therapy regimens. Furthermore, stochastic computational modeling is utilized to identify potentially vulnerable components in the network that may serve as viable candidates for drug development. Conclusion: The results presented herein can aid in the design of scientifically well-grounded targeted therapies that can be employed for the treatment of prostate cancer patients. Pribil Erica epribil8@gmail.com University of Nebraska-Lincoln 2017-05-31T11:51:08Z 2017-07-18T13:54:04Z

Prostate homeobox gene

Uniprot ID: Q99801

Gene: NKX3-1

Gene ID: 4824

 2017-07-17T17:44:11Z

Cixutumumab is a known IGFR1 inhibitor.

 2017-07-18T13:37:06Z

BKM120 also known as buparlisib is a known inhibitor of PIK3CA.

 2017-07-18T13:45:28Z

Lapatinib is a known inhibitor of ERBB2 adn EGFR. However, cancer cells have been know to acquire resistance to it.

 2017-07-18T13:37:06Z

Neuregulin 1

Uniprot ID: Q02297

Gene: NRG1

Gene ID: 3084

 2017-06-02T16:07:27Z

Phosphatase and tensin homolog

Uniprot ID: P60484

Gene Name: PTEN

Gene ID: 5728

 2017-07-18T11:11:53Z

Heparin binding EGF-like growth factor

Uniprot ID: Q99075

Gene Name: HBEGF

Gene ID: 1839

 2017-05-31T15:45:08Z

This node referes to sex hormones that are responsible for male traits. Testosterone is the most important one.

 2017-05-31T15:39:37Z

Pyrrolopyrimidine derivative and ATP-competitive inhibitor of all AKT kinases.

 2017-07-18T13:45:28Z

Enzalutamide is a drug that target/inhibit the androgen receptor.

 2017-07-18T13:53:43Z

Insulin-like growth factor

Uniprot ID: P05019

Gene: IGF1

Gene ID: 3479

 2017-06-02T16:07:45Z

Temsirolimus is a known inhibitor of mTOR.

 2017-07-18T13:53:43Z

Epidermal Growth Factor

Uniprot ID: P01133

Gene Name: EGF

Gene ID: 1950

 2017-06-02T16:08:55Z

This is a drug that is an inhibitor of MEK1.

 2017-07-18T13:45:28Z

Epidermal growth factor receptor (equivalent to EGFR).

Gene: EGFR

UniProt ID: P00533

Gene ID: 1956

 2017-07-18T11:47:15Z

Androgen Receptor Dimer

 2017-06-02T15:07:37Z

Cyclin Dependent kinase 2 - Cyclin E complex

Gene: CDK2/CCNE1

UniProt ID: P24941/P24864

Gene ID: 1017/898

 2017-05-31T16:03:33Z

growth factor receptor bound protein-2 bound to SOS

Gene: GRB2/SOS1

UniProt ID: P62993/Q07889

Gene ID: 2885/6654

 2017-05-31T15:49:33Z

B-cell lymphoma 2

Gene Name: BCL2

Uniprot ID: P10415

Gene ID: 596

 2017-05-31T16:02:00Z

Specificity protein 1

Gene: SP1

UniProt ID: P08047

Gene ID: 6667

 2017-05-31T15:56:43Z

Prostate specific antigen

Uniprot ID: P07288

Gene: KLK3

Gene ID: 354

 2017-05-31T16:02:25Z

Phosphoinositide-3,4,5-trisphosphate

 2017-07-18T11:11:53Z

Mitogen - Activated Protein Kinase Kinase 1

Gene Name: MAP2K1

Uniprot ID: Q02750

Gene ID: 5064

 2017-06-02T15:16:06Z

Insulin Receptor Substrate

Uniprot ID: P35568

Gene Name: IRS1

Gene ID: 3667

 2017-05-31T15:51:18Z

Tuberous sclerosis complex heterodimer

Uniprot ID: Q92574/P49815

Gene Name: TSC1/TSC2

Gene ID: 7248/7249

 2017-05-31T15:58:43Z

Mammalian Target of Rapamycin

Uniprot ID: P42345

Gene Name: MTOR

Gene ID: 2475

 2017-06-02T15:11:01Z

3-Phosphoinositide dependent protein kinase-1

Uniprot ID: O15530

Gene Name: PDPK1

Gene ID: 5170

 2017-07-17T17:44:11Z

small G-protein

Uniprot ID: P01112

Gene ID: 3265

Gene Name: RAS

 2017-05-31T15:52:02Z

Insulin-like growth factor-1 receptors A and B

 2017-06-02T14:42:11Z

Ribosomal protein S6 kinase beta-1

Gene Name: RPS6KB1

Uniprot ID: P23443

Gene ID: 6198

 2017-06-02T16:11:02Z

Uniprot ID: P11831/P19419

Serum Response Factor - cofactor (ELK1)

Gene: SRF/ELK1

Gene ID: 6722/2002

 2017-06-02T11:56:50Z

Androgen Receptor/ Heat Shock Protein

 2017-05-31T15:39:37Z

Extracellular adjusting protein kinase1 and 2

Uniprot ID: P27361 /P28482

Gene Name: MAPK3/MAPK1

Gene ID: 5595/5594

 2017-06-02T16:11:02Z

Cyclin-dependent kinase inhibitor 1A

Gene Name: CDKN1A

Uniprot ID: P38936

Gene ID: 1026

 2017-06-01T09:29:40Z

Proto-oncogene c-RAF

Gene Name: RAF1

Uniprot ID: P04049

Gene ID: 5894

 2017-06-02T16:10:39Z

Monomeric ras homolog

Uniprot ID: Q15382

Gene Name: RHEB

Gene ID: 6009

 2017-05-31T15:58:19Z

BCL2-associated agonist of cell death

Gene Name: BAD

Uniprot ID: Q92934

Gene ID: 572

 2017-06-01T09:29:40Z

Epidermal growth factor receptor / homologous receptor (HER2/neu)

Gene: EGFR/ERBB2

UniProt ID: P00533/P04626

Gene ID: 1956/2064

 2017-06-02T14:45:25Z

Lipid Kinase

Uniprot ID: P42336

Gene Name: PIK3CA

Gene ID: 5290

 2017-06-02T16:06:53Z

Protein Kinase B

Gene Name: AKT1

Uniprot ID: P31749

Gene ID: 207

 2017-07-17T17:44:11Z

Transmembrane protease serine 2

Uniprot ID: O15393

Gene: TMPRSS2

Gene ID: 7113

 2017-06-01T09:25:55Z

Receptor Tyrosine Kinases erbB-2/ erbB-3

Uniprot ID: P04626/P21860

Gene Name: ERBB2/ERBB3

Gene ID: 2064/2065

 2017-06-02T14:44:36Z

EGF and HBEGR are positive regulators of EFGR.

EGFR is activated by EGF through N-glycosylation.

HBEGF activates EGFR autocrinely.

 S_41 1 S_25 1

AKT and AR/HSP are positive regulators of AR/AR.

AKT activates AR/AR through phosphorylation.

Once androgens are bound to the receptor to activate it, the heat shock proteins are dissociated which allows the bound receptor to dimerize.

 S_37 1 S_24 1

p21 is a negative regulator of CDK2-CyclinE.

Increased p21 activity has been associated with decreased CDK2-Cyclin E activity.

 S_27 1

EFGR, EGFR/ERBB2, ERBB2/3, and IGFR1A/B are positive regulators of GRB2/SOS. Lapatinib inhibits EGFR/ErbB2 signaling.

EFGR binds to and activates GRB2/SOS through binding.

ERBB2/3 activates GRB2/SOS through binding.

IGFR1A/B activates GRB2/SOS through phosphorylation.

EGFR/ERBB2 activates GRB2/SOS through binding.

Lapatinib inhibits EGFR/ErbB2 signaling.

 S_1 1 S_19 1 S_32 1 S_19 1 S_18 1 S_40 1 S_19 1

BAD is a negative regulator for BCL2.

Activation of BAD, an apoptotic protein, has been associated with decreased BCL2 activity.

 S_31 1

ERK1/2 is a positive regulator of SP1.

ERK 1/2 phosphorylates SP1.

 S_26 1

AR/AR is a positive regulator of PSA. Enzalutamide is an androgen receptor signaling inhibitor.

Enzalutamide is an androgen receptor signaling inhibitor.

AR/AR binds to and activates PSA.

 S_2 1 S_34 1

PIK3KA activates PIP3. PTEN inhibits PIP3.

PTEN inhibits PIP3 through dephosphorylation, creating PIP2.

PIK3CA increase the conversion of PIP2 to PIP3.

 S_35 1 S_23 1

Raf activates MEK1.

Raf activates MEK1 through phosphorylation.

 S_29 1

IGFR1A/B activates IRS1. Cixutumumab inhibits IRS1 activation.

IGFR1A/B activates IRS1 through phosphorylation.

Cixutumumab is an IGFR1A/B inhibitor.

 S_18 1 S_8 1

AKT is a negative regulator of TSC 1/2. AZD5363 is an AKT inhibitor.

AKT phosphorylates TSC 1/2 on multiple residues including Ser939, Ser981, Ser1130, Ser1132 and Thr1462.

AZD5363 is an AKT inhibitor that inhibits the phosphorylation of AKT downstream targets.

 S_37 1 S_33 1

RHEB is a positive regulator of mTOR.

RHEB is able to bind to the mTOR kinase domain and also antagonizes a mTOR inhibitor, FKBP38.

 S_30 1

PDPK1 activates PIP3.

PIP3 phosphorylates PDPK1 at S396.

 S_11 1

GRB2/SOS is a positive regulator of Ras.

Once phosphorylation, GRB2/SOS is a complex that activates Ras.

 S_5 1

IGF activates IGFR1A/B.

IGF binds to and activates IGFR1A/B.

 S_36 1

ERK1/2, mTOR, and PDPK1 are positive regulators of RP6SKB1. Temsirolimus is a mTOR inhibitor.

ERK1/2 activates RP6SKB1 through phosphorylation.

Temsirolimus is a mTOR inhibitor.

mTOR activates RP6SKB1 through phosphorylation.

PDPK1 is known to activate a variety of kinases through phosphorylation.

 S_26 1 S_15 1 S_38 1 S_16 1

ERK1/2 with RP6SKB1 activates SRF-ELK1.

ERK1/2 phosphorylates ELK1, activating the complex.

RP6SKB1 activates SRF - ELK1 through phoshorylation.

 S_26 1 S_20 1

Once androgens are bound to the receptor to activate it, the heat shock proteins are dissociated which allows the bound receptor to dimerize.

 S_28 1

MEK1 is a positive regulator if ERK1/2. AZD6244 s an inhibitor of MAPK/ERK kinase 1/2.

AZD6244 s an inhibitor of MAPK/ERK kinase 1/2.

Inhibing MEK1 blocks the activation of ERK 1/2.

 S_12 1 S_42 1

AKT is a negative regulator of p21.

AKT inhibits p21 through cytoplasmic mislocation.

 S_37 1

Ras and PIK3CA are positive regulators of Raf. BKM120 is a PI3K inhibitor.

BKM120 is a PI3K inhibitor.

PIK3CA has been known to activate Raf.

Ras activates Raf through phosphorylation.

 S_17 1 S_35 1 S_10 1

TSC 1/2 is a negative regulator of RHEB.

Activation of TSC 1/2 is known to inhibit RHEB.

 S_14 1

AKT and RP6SKB1 are negative regulators of BAD.

When AKT activity was reduced, BAD activity was increased.

Bound RP6SKB1 (activated) has been known to inhibit BAD.

 S_20 1 S_37 1

EGF activates EGFR/ERBB2

By EGF binding to EGFR, the formation of the dimer with ERBB2 is promoted.

 S_41 1

ERBB2/3, IRS1, and Ras are positive regulators of PIK3CA.

High amounts of phosphorylated ERBB2/3 is associated with PIK3CA activity.

IRS1 binds to and activates PIK3CA.

Ras activates PIK3CA in a GTP dependent manner.

 S_40 1 S_17 1 S_13 1

NKX3 and PTEN are negative regulators of AKT. PDPK1 is a positive regulator of AKT.

PTEN and NKX3.1 are listed as positive regulators in order to match the Boolean logic AKT= (NOT NKX3.1) OR (NOT PTEN) OR (PDPK1). Setting PTEN and NKX3.1 as positive regualtors with the condition that the other two nodes are inactive enables an equivalent activity to the equation stated in the paper.

IGF induced phosphorylation of AKT is inhibited by NKX3.1.

Phosphorylated (activated) PTEN inhibits the phosphorylation of AKT at Ser473.

PDPK1 activates AKT through phosphorylation of Thr308.

 S_23 1 S_4 1 S_16 1 S_16 1 S_4 1 S_23 1 S_16 1 S_4 1 S_23 1 S_16 1

AR/AR is a positive regulator of TMPRSS2. Enzalutamide is an androgen receptor signaling inhibitor.

Enzalutamide is an androgen receptor signaling inhibitor.

AR/AR is known to activate TMPRSS2, but there is much about this interaction that is unknown.

 S_2 1 S_34 1

NRG1 activates ERBB2/3.

NRG1 activates ERBB2/3 through phosphorylation.

 S_22 1