inhibitor decreased the proliferation and migration of airway smooth muscle cells
and prevented the upregulation of contractile proteins in these cells. In conclusion, in
asthma, an increase in lysine methylation and a decrease in arginine methylation
have so far shown to be potentially beneficial treatment strategies. For COPD
nothing is known about the role of lysine methylation, but the role of arginine
methylation in COPD is starting to be explored. The first studies are showing a
beneficial effect of the restoration of arginine methylation in COPD.
4 HDACi and DNMTi in Lung Cancer
Of the different types of inhibitors described in this chapter, primarily HDACi and
DNMTi are in clinical trials for lung cancer. Alterations in DNA methylation and
protein acetylation are both considered to be major contributors to the development
and progression of lung cancer. Lung cancer is generally classified as either smallcell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), with the latter
category split into a range of other histological subtypes. NSCLC accounts for
approximately 85% of all lung cancer cases, and SCLC takes up the remaining
15% [117]. Most SCLC tumors initially respond to chemotherapy, but, unfortunately, essentially all patients experience relapse within 1 year of receiving first-line
treatment. Similar to COPD, smoking is the major risk factor for all forms of lung
cancer, particularly for SCLC.
DNMTi and HDACi have both demonstrated anticancer effects in in vitro
NSCLC studies. However, single-agent clinical trials with these inhibitors in lung
cancer patients mostly failed to show a beneficial effect. The current view is that the
combination of DNMTi or HDACi with established therapies might increase efficacy by priming cancer cells to standard chemotherapy, possibly by reactivation of
tumor suppressor genes [118]. Consequently, DNMTi and HDACi are in a host of
phase I and II clinical trials in combination therapies, for instance, with immune
checkpoint inhibitors like the monoclonal anti-PD1 antibody nivolumab. A detailed
description of these trials can be found elsewhere [119].
Interestingly, a direct link between HDACs and DNMTs exists, since it has been
found that HDACs deacetylate DNMTs [119]. In support of this, knockdown of
HDACs and treatment with a HDACi induced DNMT acetylation. Surprisingly, this
led to a decrease in DNMT levels. Overall, treatment with HDACi may thus
concomitantly decrease DNMT levels. Since increased expression of DNMTs and
HDACs crucially occurs in the oncogenic transformation of epithelia, it is therefore
speculated that HDAC inhibition may prevent lung cancer. Additionally, combinations of DNMTi and HDACi are under investigation because they may synergize in
the re-expression of silenced genes. A phase I/II trial of low-dose azacitidine
combined with entinostat in 45 extensively pretreated patients with recurrent metastatic NSCLC showed that the combination was well tolerated and objective
responses were observed [120]. This included one complete responder that was
free of disease 26 months since enrolment. The combination also compared
444
M. R. H. Zwinderman et al.
and prevented the upregulation of contractile proteins in these cells. In conclusion, in
asthma, an increase in lysine methylation and a decrease in arginine methylation
have so far shown to be potentially beneficial treatment strategies. For COPD
nothing is known about the role of lysine methylation, but the role of arginine
methylation in COPD is starting to be explored. The first studies are showing a
beneficial effect of the restoration of arginine methylation in COPD.
4 HDACi and DNMTi in Lung Cancer
Of the different types of inhibitors described in this chapter, primarily HDACi and
DNMTi are in clinical trials for lung cancer. Alterations in DNA methylation and
protein acetylation are both considered to be major contributors to the development
and progression of lung cancer. Lung cancer is generally classified as either smallcell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), with the latter
category split into a range of other histological subtypes. NSCLC accounts for
approximately 85% of all lung cancer cases, and SCLC takes up the remaining
15% [117]. Most SCLC tumors initially respond to chemotherapy, but, unfortunately, essentially all patients experience relapse within 1 year of receiving first-line
treatment. Similar to COPD, smoking is the major risk factor for all forms of lung
cancer, particularly for SCLC.
DNMTi and HDACi have both demonstrated anticancer effects in in vitro
NSCLC studies. However, single-agent clinical trials with these inhibitors in lung
cancer patients mostly failed to show a beneficial effect. The current view is that the
combination of DNMTi or HDACi with established therapies might increase efficacy by priming cancer cells to standard chemotherapy, possibly by reactivation of
tumor suppressor genes [118]. Consequently, DNMTi and HDACi are in a host of
phase I and II clinical trials in combination therapies, for instance, with immune
checkpoint inhibitors like the monoclonal anti-PD1 antibody nivolumab. A detailed
description of these trials can be found elsewhere [119].
Interestingly, a direct link between HDACs and DNMTs exists, since it has been
found that HDACs deacetylate DNMTs [119]. In support of this, knockdown of
HDACs and treatment with a HDACi induced DNMT acetylation. Surprisingly, this
led to a decrease in DNMT levels. Overall, treatment with HDACi may thus
concomitantly decrease DNMT levels. Since increased expression of DNMTs and
HDACs crucially occurs in the oncogenic transformation of epithelia, it is therefore
speculated that HDAC inhibition may prevent lung cancer. Additionally, combinations of DNMTi and HDACi are under investigation because they may synergize in
the re-expression of silenced genes. A phase I/II trial of low-dose azacitidine
combined with entinostat in 45 extensively pretreated patients with recurrent metastatic NSCLC showed that the combination was well tolerated and objective
responses were observed [120]. This included one complete responder that was
free of disease 26 months since enrolment. The combination also compared
444
M. R. H. Zwinderman et al.