Page 23 - Read Online

Kaehler et al. Cancer Drug Resist 2019;2:18-30 I http://dx.doi.org/10.20517/cdr.2019.05 Page 23

Promising variants as new predictive factors
Within the last years, several studies revealed novel promising candidates hereditary variants apart
from ADME genes that might help to predict ADE under chemotherapy regimen. For these, we would
like to stress some recent findings in anthracycline-derived cardiotoxicity and L-asparaginase-induced
hypersensitivity reactions.

Anthracylines, e.g., doxorubicin or daunorubicin, are of major relevance for the treatment of multiple solid
tumors and leukemia. Severe side effects, in particular cardiotoxicity occurring in about 57% of all patients
is a frequent dose limiting cause. In the last years, several studies have shown hereditary variants in UDP-
glucuronosyltransferase 1A6 (UGT1A6; taq marker of UGT1A6*4, rs17863783), the nucleoside transporter
SLC28A3 (L461L, rs7853758; intronic variant, rs885004) or retinoic acid receptor gamma (RARγ; rs2229774)
[54]
as promising predictive biomarkers (comprehensively reviewed in ). The silent variant V209V (rs17863783)
in UGT1A6 was associated with increased risk of anthracycline-induced cardiotoxicity in several patient
cohorts, potentially resulting in decrease of enzyme function and accumulation of toxic metabolites [55,56] . A
similar phenomena has been shown for the sodium-coupled nucleoside transporter SLC28A3, as rs7853758
[57]
and rs885004 might interfere with enzyme activity promoting risk of cardiotoxicity . In addition, the
amino acid exchange S427L (rs2229774) in retinoic acid receptor gamma (RARγ) was found in a GWAS
study to be associated with cardiotoxic risk increase in children . Earlier studies reported an association
[58]
[59]
of ABCC1 efflux transporter variants with doxorubicin-associated cardiomyopathy . However, so far
the predictive value of these variants is not determined or low, preventing its implementation into clinical
practice so far.

Regarding the use of L-asparaginase in ALL, hypersensitivity reaction have been observed. Interestingly,
pharmacogenetics studies revealed an association to multiple polymorphisms (rs4958351, rs10070447,
rs6890057, rs4958676, rs6889909, rs11167640, rs10072570, rs13354399, rs17356099, rs2055083, rs707176) in
the AMPA 1 glutamate receptor (GRIA1) [60,61] . These data clearly point to inherited factors contributing to
treatment hypersensitivity, however, functional validation is necessary to understand the relevance of these
variants.

Finally, the treatment of solid tumors with taxanes, such as paclitaxel, docetaxel, and cabazitaxel is commonly
associated with treatment-limiting peripheral sensory neuropathy. Currently there are no biomarkers
[62]
available, allowing a precise prediction of such chemotherapy-induced peripheral neuropathy (CIPN) . The
attempt to reveal predictive genetic markers through GWAS studies disclosed an intronic SNP (rs875858,
MAF ¼ 0.056), in the VAC14 gene. VAC14 encodes a scaffold protein that is a component of the PIKfyve
protein kinase complex. Interestingly this complex is involved in the synthesis of phosphatidylinositol
[63]
3,5-bisphosphate. Knock-out experiments in mice caused severe neurodegeneration . The authors of the
GWAS study further made mechanistic approaches to validate the functional consequences of the VAC14
variant. iRNA knockdown of VAC14 in stem cell-derived peripheral neuronal cells increased docetaxel
sensitivity and VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type controls. Further
GWAS meta-analyses of taxane-related CIPN were however not able to identify significant associations of any
genetic variant to ≥ grade common terminology criteria for adverse events (CTCAE) neuropathy in European
[64]
and African Americans after correction for multiple testing . Concluding, there are some interesting genetic
risk candidates, however their suitability for predicting treatment-limiting peripheral sensory neuropathy has
not been confirmed so far.

mUlTIDRUg ResIsTaNCe IN CaNCeR TReaTmeNT aND ITs phaRmaCOgeNeTIC

CONTRIbUTIONs
[65]
The term “multidrug resistance” is tightly linked to expression of ABC-transporters in cancer cells . By
efflux of substrates across the membrane, the intracellular level of the drug is lowered and drug resistance