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Page 228 Mini et al. Cancer Drug Resist 2020;3:225-31 I http://dx.doi.org/10.20517/cdr.2020.10

including acute lymphoblastic leukemia (ALL), and azathioprine, which is used as immunosuppressive
agent in the treatment of autoimmune diseases and in regimens to prevent transplant rejection.
Catabolism of thiopurines is mediated by xanthine oxidase and TPMT, being the latter responsible for
their main inactivation pathway. The wide use of mercaptopurine in pediatric ALL in combination with
other anticancer drugs, along with the established role of TPMT genetic variants in mercaptopurine-
related toxicities, has led through the years to the definition of national and international guidelines
[20]
that are nowadays commonly followed . More recently, clinical guidelines are also available for nudix
[20]
hydrolase 15 (NUDT15) polymorphisms . This is a ubiquitously expressed nucleotide triphosphate
diphosphatase enzyme that inactivates triphosphate thionucleotides. In patients carrying deleterious
NUDT15 polymorphisms, increased toxic levels of thionucleotides are achieved after mercaptopurine
treatment. Other enzymes, such as inosine triphosphate pyrophosphatase that catalyzes the hydrolysis of
the triphosphate moieties from noncanonical (deoxy-) purine triphosphate, protein kinase C, and casein
kinase substrate in neurons protein 2 (PACSIN2), a protein close to membranes, have been suggested to
play a role in thiopurine adverse events but further investigation is required.

[21]
By keeping the focus on hemolymphoid cancers, Abaji and Krajinovic discussed the pharmacogenetics
of asparaginase, a drug used in these diseases, in particular in ALL. Although its mechanism of action
is still not fully clarified, the main evidence suggests its involvement in the hydrolysis of asparagine and
glutamine in serum. Due to the xenobiotic nature of asparaginase, hypersensitivity reactions represent a
quite common adverse event, counteracted to a relevant extent by premedication treatment. From GWAS
studies, genes whose polymorphisms could play a role in this toxic event have emerged [e.g., polypeptide
N-acetylgalactosaminyltransferase 10 (GALNT10)]. In addition, polymorphisms in HLA Class II region
alleles have been associated with hypersensitivity related to asparaginase. For other adverse events, such
as pancreatitis or thrombosis, genetic polymorphisms identified by candidate gene or GWAS approaches
have been reported [e.g., unc-51-like autophagy activating kinase (ULK2) and nuclear factor of activated
T cells 2 (NFATC2)]. Correlations between asparaginase efficacy and genetic polymorphisms have
also been described [e.g., asparagine synthetase (ASNS) activating transcription factor 5 (ATF5) and
argininosuccinate synthase 1 (ASS1)]. However, relationships between asparaginase toxicity/efficacy and
germline polymorphisms have still not been validated; thus, guidelines on this associations are lacking.

Differently from cytotoxic anticancer drugs, most of the evidence for pharmacogenetics of targeted agents
refers to efficacy more than toxicity and commonly to tumor genome more than host genome. This is the
[22]
case of MoAbs, including immune checkpoint inhibitors, as reviewed by Shek et al. . Polymorphisms in
genes codifying target proteins or protein substrates in the signaling pathways of MoAbs (e.g., vascular
endothelial growth factor and RAS) as well as polymorphisms in genes codifying proteins involved in
ADME of MoAbs have been shown to play a role in their efficacy [e.g., Fc fragment of IgG receptor IIIa
(FCGR3A) gene polymorphisms]. More recently, polymorphisms in immune checkpoint genes [e.g.,
cytotoxic T-lymphocyte associated protein 4 (CTLA4), CD274 molecule, and PD-L1] have also been linked
to the efficacy of immune checkpoints inhibitors. The presence of such polymorphisms impairs or strongly
decreases the response to MoAbs. This field of cancer therapeutics, which is probably the most promising,
could greatly benefit from the implementation of next generation sequencing approaches in clinical
practice prior to treatment initiation.

[23]
The review of Murthy and Muggia describes clinical trials that have led to the approval of PARP
inhibitors in BRCA-mutated ovarian and breast cancers (to which pancreatic cancer was added in
December 2019), pharmacological differences between the various PARP inhibitors, and the emerging
mechanisms of resistance. The authors focused on the targets of these drugs (mainly, PARP1 and PARP2
but also PARP1-3 for some of them) as well as on the pharmacological role. This review provides an
overview for future development of these drugs. Due to the frequent occurrence of tumor drug resistance,