support the application of PI3K inhibitors combined with endocrine therapy in this
genetic background [160].
Nearly all hallmarks of cancer can be targeted by approved protein kinase
inhibitors. However, there are currently no FDA-accepted kinase inhibitors influencing genome instability and DNA damage response. The success story of olaparib, a
Poly [ADP-ribose] polymerase 1 (PARP-1) inhibitor, underlines the high potential
of small molecules in this field. In general, the incidence of DNA single- or doublestrand breaks is mainly controlled by the network of ATR/ATM and CHK1/CHK2
signaling pathways leading to active DNA repair mechanisms and cell cycle checkpoint regulation [161]. At the moment, two different ATR inhibitors, AZD6738 and
M6620, are tested in clinical phase-II trials with four and six studies. They are
administered in prostate cancer, CLL, recurrent ovarian cancer, progressive metastatic gastric or gastroesophageal junction cancer, small cell lung carcinoma, as well
as metastatic tumors including RCC, urothelial carcinoma, ovarian cancer, and
PDAC [NCT03787680, NCT03328273, NCT03641313, NCT03517969,
NCT03682289, NCT02595892, NCT02567409, NCT03462342, NCT02627443,
NCT02487095].
Furthermore, checkpoint kinases are valid targets in DNA damage response. The
CHK1/CHK2 inhibitor prexasertib is tested in small cell lung cancer, ovarian cancer,
breast cancer, and prostate cancer in phase-II clinical trials [NCT02735980,
NCT03414047, NCT02873975, NCT02203513] (Fig. 7).
In BRCA wild-type recurrent high-grade serous ovarian cancer, prexasertib could
exhibit clinical activity and was in general well tolerated by treated patients
[162]. Particularly patients with platinum-resistant or platinum-refractory cancer
could profit here from further drug development [162].
9 Challenges
Beside numerous advances of kinase inhibitors, profound understanding of mechanisms in vivo is needed to overcome actual limitations in clinical oncology [13].
Secondary therapy resistance based on kinase mutations is an abundant phenomenon arising after kinase inhibition [163]. The diversity of such mutations among
different kinases hampers the overall treatment success in cancer patients
[164]. Acquired resistance is the most common resistance type caused by kinase
inhibitors and relates to tumors that respond to therapy initially but show posterior
resistance to permanent delivered therapy [13]. Secondary resistance can be induced
by changes in the kinase gatekeeper residue since hydrophobic interactions in the
sub-pocket are decisive for the inhibitor binding affinity [165, 166]. The gatekeeper
residue interacts with Type I and Type II kinase inhibitors and sterically influences
inhibitor binding to the hydrophobic region in the binding pocket [167]. In addition
to gatekeeper mutations in BCR-ABL kinases inducing imatinib resistance, numerous other targets are affected by gatekeeper mutations [168–173]. A prominent
example is the T790M mutation in EGFR kinase leading to boosted affinity toward
Exploiting Kinase Inhibitors for Cancer Treatment: An Overview of Clinical. . .
143
genetic background [160].
Nearly all hallmarks of cancer can be targeted by approved protein kinase
inhibitors. However, there are currently no FDA-accepted kinase inhibitors influencing genome instability and DNA damage response. The success story of olaparib, a
Poly [ADP-ribose] polymerase 1 (PARP-1) inhibitor, underlines the high potential
of small molecules in this field. In general, the incidence of DNA single- or doublestrand breaks is mainly controlled by the network of ATR/ATM and CHK1/CHK2
signaling pathways leading to active DNA repair mechanisms and cell cycle checkpoint regulation [161]. At the moment, two different ATR inhibitors, AZD6738 and
M6620, are tested in clinical phase-II trials with four and six studies. They are
administered in prostate cancer, CLL, recurrent ovarian cancer, progressive metastatic gastric or gastroesophageal junction cancer, small cell lung carcinoma, as well
as metastatic tumors including RCC, urothelial carcinoma, ovarian cancer, and
PDAC [NCT03787680, NCT03328273, NCT03641313, NCT03517969,
NCT03682289, NCT02595892, NCT02567409, NCT03462342, NCT02627443,
NCT02487095].
Furthermore, checkpoint kinases are valid targets in DNA damage response. The
CHK1/CHK2 inhibitor prexasertib is tested in small cell lung cancer, ovarian cancer,
breast cancer, and prostate cancer in phase-II clinical trials [NCT02735980,
NCT03414047, NCT02873975, NCT02203513] (Fig. 7).
In BRCA wild-type recurrent high-grade serous ovarian cancer, prexasertib could
exhibit clinical activity and was in general well tolerated by treated patients
[162]. Particularly patients with platinum-resistant or platinum-refractory cancer
could profit here from further drug development [162].
9 Challenges
Beside numerous advances of kinase inhibitors, profound understanding of mechanisms in vivo is needed to overcome actual limitations in clinical oncology [13].
Secondary therapy resistance based on kinase mutations is an abundant phenomenon arising after kinase inhibition [163]. The diversity of such mutations among
different kinases hampers the overall treatment success in cancer patients
[164]. Acquired resistance is the most common resistance type caused by kinase
inhibitors and relates to tumors that respond to therapy initially but show posterior
resistance to permanent delivered therapy [13]. Secondary resistance can be induced
by changes in the kinase gatekeeper residue since hydrophobic interactions in the
sub-pocket are decisive for the inhibitor binding affinity [165, 166]. The gatekeeper
residue interacts with Type I and Type II kinase inhibitors and sterically influences
inhibitor binding to the hydrophobic region in the binding pocket [167]. In addition
to gatekeeper mutations in BCR-ABL kinases inducing imatinib resistance, numerous other targets are affected by gatekeeper mutations [168–173]. A prominent
example is the T790M mutation in EGFR kinase leading to boosted affinity toward
Exploiting Kinase Inhibitors for Cancer Treatment: An Overview of Clinical. . .
143