Genetika, biochemie, patofyziologie

Defects in pathways regulating DNA repair

Synonyma

• HRR-mutations - Homologous recombinant repair mutations -
• DDR mutations
• Deleterious aberrations in genes involved in DNA repair by homologous recombination
• Homologous recombination deficiency (HRD)

Geny těchto metabolických drah

• BRCA2 (Breast Cancer Gene 2)
• BRCA1 (Breast Cancer Gene 1)
• ATM (Mutated in Ataxis Telangieectasia) alterations
• PALB2
• FANCA
• CHEK2
• CDK12 [5]

Význam

• Might be associated with poorer outcomes in patients treated with abiraterone/enzalutamide [5]
• Mutations associate with a worse prognosis
• Aberrations being inherited in approximately 10% to 12% of men with lethal prostate cancer [5]

BRIP1 alteration

CDK12-mutated group

E26 transformation-specific (ETS) fusions

Elevated basal autophagy

• Protects prostate cancer cells from cytotoxic treatments [6]

FOXA1

• Point mutations

Heterozygous deletion of chromosome 17p (17p)

• One of the most frequent genomic events in human cancers
• Cca 20-megabase deletion region of 17p
• In 63% of metastatic castration-resistant prostate cancer (CRPC) includes:

• Tumor suppressor TP53

• POLR2A gene encoding the catalytic subunit of RNA polymerase II (RNAP2) [7]

• Heterozygous loss of 17p
• Confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1)
• RBX1 activates POLR2A by the K63-linked ubiquitination
• Thus elevates the RNAP2-mediated mRNA synthesis [7]

• Combined inhibition of RNAP2 and RBX1
• Profoundly suppress the growth of CRPC in a synergistic manner
• Potentiates the therapeutic effectivity of the RNAP2 inhibitor
• Alpha-amanitin-based antibody drug conjugate (ADC) [7]
• Alpha-amanitin-conjugated anti-EpCAM antibodies [7]

POLR2A

• Catalytic subunit of the RNAP2 complex
• In charge of mRNA synthesis in cells
• POLR2A and RNAP2 activity is specifically inhibited by alpha-amanitin
• Small molecule peptide produced by the death cap mushroom (Amanita phalloides)
• Inhibition of POLR2A with alpha-amanitin-based ADC
• Selectively suppresses the proliferation, survival and tumor growth of CRPC cells [7]

MLH1

MSH2

MSH6

MYC

• Copy number alterations involving
• C-MYC alterations occur in about 20% of mCRPC [9]
• C-MYC transcript levels are increased in AR-V7–high bone metastases [9]
• Overexpression of c-MYC protein was shown to induce androgen-independent growth [9]
• Potential involvement of c-MYC in alternative splicing and generation of AR-V7 has also been suggested [9]
• C-MYC overexpression is associated with
• Pathway enrichment for FA metabolism in cell lines, murine models, and human prostate tumors [9]
• FASN expression was also increased in c-MYC–transformed cells [9]
• MYC-CaP cells were very sensitive to FASN inhibition with IPI-9119 [9]
• Suggesting a mutual regulation between FASN and c-MYC [9]

PMS2

PTEN

• Copy number alterations involving

RB1

• Copy number alterations involving

RUNX2

• Transcription factor
• Prevents cancer cells from undergoing apoptosis
• Thereby contributing to the development of prostate cancer [11]

SPOP

• Point mutations

TP53

• Point mutations
• TP53 loss may play a dominant role in the tumor initiation or progression
• Unclear whether many genes in the deletion region impact tumorigenesis beyond TP53 loss alone [7]

Upregulation of lipogenic enzymes

• Lipin-13 [6]

BRCA1/2 mutations

• BRCA2—are associated with increased tumor aggressiveness [4]

FANCA alteration

Prostate cancerNote GLS is highly expressed in prostate cancers and positively correlates with tumor state and progression. In glutamine addicted prostate cancer cells, GLS regulates glucose uptake through inhibition of thioredoxin-interacting protein ( TXNIP) expression, a potent negative regulator of aerobic glycolisis and glucose uptake. When GLS activity was suppressed by siRNA or BPTES, TXNIP was remarkably induced and the invasive capacity of these cells significantly reduced (Pan et al., 2015). It was in these tumors that MYC, which contributes to their initiation and progression (Koh et al., 2010), was described to upregulate GLS expression through suppression of MIR-23a/b (Gao et al., 2009). Recent results show that GLS is highly expressed in large extracellular vesicles (LEVs) extruded from prostate cancer cells (Minciacchi et al., 2015). Release of these vesicles is dependent on glutamine metabolism. Thus, a significant reduction in the production of LEVs is observed when these cells are treated with BPTES (Dorai et al., 2018). [1]

GLS

• Interact with peroxisome proliferator-activated receptor gamma ( PPARG) in the nuclei of prostate cancer cells
• Interaction decreased the nuclear receptor activity (de Guzzi Cassago et al., 2018) [1]

Lipin-1 zvýšená aktivita

• Enzyme participating to lipid anabolism
• Regulating cancer cell phenotype and metabolism
• Lipins can regulate various cellular processes including
• Gene expression,
• Proliferation,
• Migration
• Autophagy [6]

Phosphatidate phosphatase (PAP) activity

• Generating diacylglycerol (DAG) from phosphatidic acid (PA)
• Contribute to the fusion of autophagosomes with lysosomes
• Autophagy clearance [6]

Upregulation of lipogenic enzymes

• Upregulation of de novo lipogenesis
• Provide substrates and fuel for metastatic spread
• Whether increased levels of fats affect AR signaling to promote an aggressive disease remains to be determined
• Selective and potent inhibitor of fatty acid synthase
• Inhibits AR
• Most importantly AR-V7
• Reduces mCRPC growth
• Potential mechanism to overcome resistance to AR inhibitors
• Overwhelming majority of human CRPC metastases we examined coexpressed FASN and AR-FL [9]
• FASN was consistently coexpressed with AR-V7 [9]

• Prostate cancer (PCa) progression is marked by
• Increasing rates of de novo FA synthesis
• Independent of circulating lipid levels [9]

Lipin-13 [6]

Fatty acid synthase (FASN)

• Overexpression
• Key enzyme in de novo fatty acid synthesis [9]
• In human mCRPC
• Both FASN and AR-FL were detected in 87% of metastases
• Catalyzes the synthesis of palmitate from malonyl-CoA and acetyl-CoA using NADPH as the reducing agent
• Enhanced FASN activity is also associated with several oncogenic mechanisms
• Activation of the PI3K/Akt/mTORC1 pathway
• Palmitoylation of known oncogenes including k-RAS and WNT-1
• Regulation of endoplasmic reticulum (ER) function to sustain membrane biogenesis
• Resistance to genotoxic insults
• FASN overexpression is linked to resistance to chemotherapy
• FASN expression is transcriptionally induced by AR
• Through the activation of SREBP1
• By a direct binding to FASN promoter regions [9]

Enzymes in the lipogenic pathway

Sterol regulatory element-binding proteins (SREBPs)

• Transcriptional regulators
• Significantly increased in PCa, especially in the mCRPC
• SREBP1 inhibition can down-regulate AR-FL levels
• Mutual regulation between AR signaling and FA metabolism [9]

Tumor suppressor genes loss

• PTEN (gene)
• Up to 70 % of men with prostate cancer
• Have lost one copy of the PTEN gene at the time of diagnosis
• KAI1
• E-cadherin
• CD44 [11]

Prostate cancer (PCa) metastasizes to bone and soft tissues

• Greatly decreasing quality of life,
• Causing bone pain,
• Skeletal complications, and mortality in PCa patients.

“cross-talk” between cancer cells and their microenvironment

• Recruitment and reprogramming of bystander and dormant cells (DCs) by a population of metastasis-initiating cells (MICs)
• Recruited and reprogrammed DCs gain MICs phenotypes
• Can subsequently metastasize to bone and soft tissues
• MICs can also recruit and reprogram circulating tumor cells (CTCs)
• Could contribute to cancer cell evolution
• Acquisition of therapeutic resistance

Vitamin C

• Preventivní vliv nebyl v případě karcinomu prostaty prokázá [15]

Vitamíny řady B a homocystein

• Souvislost mezi karcinomem prostaty a sérovou hladinou kyseliny listové, vitaminu B6, B12 a homo-cysteinem nebyla prokázána [15]