158. Mukherjee B et al (2012) The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of
ATM-and DNA-PKCs-mediated DNA damage responses. Neoplasia 14:34
159. Bauer TM, Patel MR, Infante JR (2015) Targeting PI3 kinase in cancer. Pharmacol Ther
146:53–60
160. Di Leo A et al (2018) Buparlisib plus fulvestrant in postmenopausal women with hormonereceptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR
inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet
Oncol 19(1):87–100
161. Manic G et al (2015) Trial watch: targeting ATM-CHK2 and ATR-CHK1 pathways for
anticancer therapy. Mol Cell Oncol 2(4):e1012976
162. Lee J-M et al (2018) Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA
wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase
2 study. Lancet Oncol 19(2):207–215
163. Wilson TR et al (2012) Widespread potential for growth-factor-driven resistance to anticancer
kinase inhibitors. Nature 487:505
164. Lito P, Rosen N, Solit DB (2013) Tumor adaptation and resistance to RAF inhibitors. Nat Med
19:1401
165. Chell V et al (2013) Tumour cell responses to new fibroblast growth factor receptor tyrosine
kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of
acquired resistance. Oncogene 32:3059
166. Foguel D et al (2014) The importance of a gatekeeper residue on the aggregation of
transthyretin implications for transthyretin-related amyloidoses. J Biol Chem 289
(41):28324–28337
167. Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2:358–364
168. Gibbons DL et al (2012) The rise and fall of gatekeeper mutations? The BCR-ABL1 T315I
paradigm. Cancer 118:293
169. Heinrich MC et al (2006) Molecular correlates of imatinib resistance in gastrointestinal stromal
tumors. J Clin Oncol 24:4764
170. Metzgeroth G et al (2012) Limited clinical activity of nilotinib and sorafenib in FIP1L1PDGFRA positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation.
Leukemia 26:162
171. Nishikawa S et al (2018) Selective gene amplification to detect the T790M mutation in plasma
from patients with advanced non-small cell lung cancer (NSCLC) who have developed
epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. J Thorac
Dis 10(3):1431–1439
172. Pauwels D, Sweron B, Cools J (2012) The N676D and G697R mutations in the kinase domain
of FLT3 confer resistance to the inhibitor AC220. Haematologica 97:1773
173. Xavier CP et al (2009) Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation
and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells.
Cancer Lett 281:162
174. Kobayashi S et al (2005) EGFR mutation and resistance of non–small-cell lung cancer to
gefitinib. N Engl J Med 352:786
175. Pao W et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is
associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73
176. Yun CH et al (2008) The T790M mutation in EGFR kinase causes drug resistance by
increasing the affinity for ATP. Proc Natl Acad Sci 105:2070
177. Heymach JV et al (2006) Epidermal growth factor receptor inhibitors in development for the
treatment of non–small cell lung cancer. Clin Cancer Res 12:4441s
178. Kwak EL et al (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired
resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665
179. Modugno M et al (2007) Crystal structure of the T315I Abl mutant in complex with the aurora
kinases inhibitor PHA-739358. Cancer Res 67:7987
152
A. Moschopoulou et al.
ATM-and DNA-PKCs-mediated DNA damage responses. Neoplasia 14:34
159. Bauer TM, Patel MR, Infante JR (2015) Targeting PI3 kinase in cancer. Pharmacol Ther
146:53–60
160. Di Leo A et al (2018) Buparlisib plus fulvestrant in postmenopausal women with hormonereceptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR
inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet
Oncol 19(1):87–100
161. Manic G et al (2015) Trial watch: targeting ATM-CHK2 and ATR-CHK1 pathways for
anticancer therapy. Mol Cell Oncol 2(4):e1012976
162. Lee J-M et al (2018) Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA
wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase
2 study. Lancet Oncol 19(2):207–215
163. Wilson TR et al (2012) Widespread potential for growth-factor-driven resistance to anticancer
kinase inhibitors. Nature 487:505
164. Lito P, Rosen N, Solit DB (2013) Tumor adaptation and resistance to RAF inhibitors. Nat Med
19:1401
165. Chell V et al (2013) Tumour cell responses to new fibroblast growth factor receptor tyrosine
kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of
acquired resistance. Oncogene 32:3059
166. Foguel D et al (2014) The importance of a gatekeeper residue on the aggregation of
transthyretin implications for transthyretin-related amyloidoses. J Biol Chem 289
(41):28324–28337
167. Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2:358–364
168. Gibbons DL et al (2012) The rise and fall of gatekeeper mutations? The BCR-ABL1 T315I
paradigm. Cancer 118:293
169. Heinrich MC et al (2006) Molecular correlates of imatinib resistance in gastrointestinal stromal
tumors. J Clin Oncol 24:4764
170. Metzgeroth G et al (2012) Limited clinical activity of nilotinib and sorafenib in FIP1L1PDGFRA positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation.
Leukemia 26:162
171. Nishikawa S et al (2018) Selective gene amplification to detect the T790M mutation in plasma
from patients with advanced non-small cell lung cancer (NSCLC) who have developed
epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. J Thorac
Dis 10(3):1431–1439
172. Pauwels D, Sweron B, Cools J (2012) The N676D and G697R mutations in the kinase domain
of FLT3 confer resistance to the inhibitor AC220. Haematologica 97:1773
173. Xavier CP et al (2009) Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation
and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells.
Cancer Lett 281:162
174. Kobayashi S et al (2005) EGFR mutation and resistance of non–small-cell lung cancer to
gefitinib. N Engl J Med 352:786
175. Pao W et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is
associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73
176. Yun CH et al (2008) The T790M mutation in EGFR kinase causes drug resistance by
increasing the affinity for ATP. Proc Natl Acad Sci 105:2070
177. Heymach JV et al (2006) Epidermal growth factor receptor inhibitors in development for the
treatment of non–small cell lung cancer. Clin Cancer Res 12:4441s
178. Kwak EL et al (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired
resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665
179. Modugno M et al (2007) Crystal structure of the T315I Abl mutant in complex with the aurora
kinases inhibitor PHA-739358. Cancer Res 67:7987
152
A. Moschopoulou et al.