Table 1 The key pathogenic pathways in ENKTL are described with a summary of the specific molecular/genetic abnormalities involved in each pathway. Evidence for each pathway as a therapeutic target is indicated where applicable

Sustaining proliferative signaling

JAK/STAT

Upregulated via mutation or phosphorylation

Huang et al. [5, 80]

Anti-tumor activity of JAK-3 and STAT-3 inhibition in pre-clinical / in vitro models. Clinical trials evaluating JAK inhibitors in ENKTL ongoing.

Nairismagi et al. [24]

Sim et al. [19]

RUNX3

Upregulated and has oncogenic role promoting proliferation and survival in ENTKL.

Selvarajan et al. [44]

MYC inhibition in vitro leads to down-regulation of RUNX3 and apoptosis, suggesting MYC as potential therapeutic target.

Selvarajan et al. [44]

EZH2

Upregulated and functions as a transcriptional co-activator via a non-canonical pathway.

Yan et al. [27]

Targeting EZH2 using a PCR2 inhibitor induces apoptosis in ENKTL.

Yan et al. [28]

NF-kB

Upregulated and promotes survival and proliferation.

Huang et al. [5, 80]

Bortezomib in ongoing early phase clinical trials for ENKTL.

Liu et al. [32]

Ng et al. [7, 41]

Tang et al [36]

Chen et al. [35]

AURKA

Upregulated, promotes cell proliferation.

Iqbal et al. [6]

In vitro inhibition of AURKA induced apoptosis

Iqbal et al. [6]

Ng et al. [7, 41]

PDGFRα

Upregulated. Mediates migration, proliferation and cell survival.

de Mel et al. [162]

Potential therapeutic target for tyrosine kinase inhibitors.

Huang et al. [5, 80]

NOTCH

Upregulated in ENKTL, involved in developmental processes and cancer.

Huang et al. [5, 80]

Potential therapeutic target for NOTCH inhibitors.

Aster et al. [163]

CDK2, HSPCA

Upregulated. Promotes proliferation and survival of cancer cells.

Zhang et al. [164]

N/A

N/A

DDX3X

RNA helicase, loss of function mutations lead to cell cycle progression and activation of other pro-proliferative pathways

Jiang et al [18]

N/A

N/A

Evading Growth Supressors /Resisting Cell Death

Survivin

Upregulated in the majority of ENKTL. Inhibits apoptosis.

Ng et al. [7, 41]

Survivin inhibition in vitro induced apoptosis, suggesting potential therapeutic role.

Ng et al. [7, 41],

Ng et al. [165]

de Mel et al. [162]

P53

Upregulated (e.g. by mutation). Inhibits apoptosis.

Ng et al. [7, 41]

N/A

N/A

Quintanilla Martinez et al. [66]

BIRC1, IL-1A, TNFRS10D

Upregulated, inhibits apoptosis.

Zhang et al. [164]

N/A

N/A

PTPRK

Frequently deleted and hypermethylated. Re expression suppressed proliferation and induced apoptosis. Precise function under evaluation

N/A

N/A

PRDM1

Frequently deleted in and re expression leads to cell growth. Functional role under investigation.

N/A

N/A

FOXO3

Frequently deleted in apoptosis induced by re-expression. Function under investigation

N/A

N/A

HACE1

Encodes E3 ubiquitin ligase, frequently deleted and hypermethylated. Function Under investigation

N/A

N/A

ATG5

Candidate tumour suppressor gene awaiting evaluation of function.

N/A

N/A

AIM1

Candidate tumour suppressor gene awaiting evaluation of function.

N/A

N/A

Autophagy pathway

Beclin 1 under-expression is associated with a worse prognosis

Huang et al. [5, 80]

Response to HDAC inhibition in combination with bortezomib in two patients with RR ENKTL.

Tan et al. [81]

Immune Evasion

PD-L1

Upregulated. Involved in immune evasion.

Ng et al. [3, 116]

Patients with relapsed ENKTL showed response to pembrolizumab, an antibody against PD1.

Kwong et al. [11]

de Mel et al. [162]

Genomic Instability/Deregulated DDR

ATR

Deregulation (e.g. deletion) resulting in abnormal DNA damage response.

Liu et al. [123]

N/A

N/A

Angiogenesis

VEGF

Upregulated. Promotes tumour vascularization and growth.

Jørgensen et al. [127], de Mel et al. [162]

Potential therapeutic target.

Jørgensen et al. [127]

 Epigenetic Deregulation

Promoter Hypermethylation

Widespread promoter hypermethylation leading to down regulation of tumor suppressor genes.

Kucuk et al. [20]

N/A

N/A

BCOR

Interacts with HDAC family. Role in ENKTL under evaluation

Huynh et al. [157]

N/A

N/A

MLL2

Histone methyltransferase. Role in ENKTL under evaluation

Milne et al. [158]

N/A

N/A

miR-150

Downregulated of miRNAs in ENKTL. Targets of these miRNAs include genes in critical pathways such as p53, MAPK and EZH2

Ng et al. [7, 41]

N/A

N/A

miR-101

miR-26a

miR-26b

miR-28-5

miR-363

miR-146

miR-21

Upregulated and have a pro-oncogenic function

Yamanaka et al. [59]

N/A

N/A

miR-155

miR-146a

Downregulated, associated with poor prognosis

Paik et al. [104]

N/A

N/A

miR-221

Upregulated, associated with poor prognosis.

Guo et al. [166]

N/A

N/A

 EBV Mediated Mechanisms

EBV lytic genes (BHRF1, BKRF3, BZLF1)

Upregulated. Potential pathogenic role in ENKTL . BHRF1 may have anti-apoptotic role due to sequence homolog to human BCL-2.

Zhang et al. [164]

N/A

N/A

 CD38

CD38

Upregulated. Exact role unknown but associated with poorer prognosis.

Hu et al. [167]

Good in-vitro efficacy of daratumumab and one case report documenting complete response.

Mustafa et al. [153]

Hari et al. [154]