Targeting Homologous Recombination Repair in Cancer - DNA Repair in Cancer Therapy - page 136

TABLE 7.3 Potential Inhibitors of HRR and Clinical Application

Putative/established HRR
inhibitor Target HRR process inhibited Clinical use *

DNA DAMAGE SIGNALING/REPAIR

KU55933 (AstraZeneca) ATM kinase ATM-dependent HRR at forks

and in G2 phase

Unknown

AZD7762 (AstraZeneca);
PF-00477736 (Pfizer);
XL844 (Exelixis)

Chk1 kinase ( þ /- Chk2) ATR/Chk1-dependent HRR In phase I, typically in combination with

gemcitabine in solid tumors

Mirin MRN MRN dependent end-

processing and HRR protein
recruitment

Unknown

Curcumin FA pathway FANCD2-dependent HRR Multiple phase II/II trials particularly in

gastrointestinal cancers, also in combination
with IR

Various HDAC inhibitors HDAC9/10 Unknown mechanism Several trials with HDAC inhibitors but none

specific for HDAC9/10

SIGNAL TRANSDUCTION PATHWAYS

Imatinib (Novartis) c-Abl kinase RAD51 stimulation by c-Abl

kinase or BCR/ABL oncogene

Numerous trials including phase III in
multitude of solid tumors and hematopoetic
malignancies

Erlotinib (Genentech),
gefinitib (Astra Zeneca)

EGFR RAD51 expression through

unknown mechanism

Multiple phase II/III trials in monotherapy or
combination in non-small cell lung cancer

MP-470 (SuperGen) Multiple targets

including c-Met kinase

RAD51 expression through
unknown mechanism

Phase I in monotherapy or combination for
solid tumors and lymphoma completed

OTHER CELLULAR PROCESSES

IPI-540 (Infinity); STA-9090
(Synta)

HSP90 Possible downregulation of

FANCA, BRCA1, RAD51

As monotherapy or combination therapy in
multiple solid and hematopoetic cancers

Bortezomib Ubiquitine proteasome Probably interference with

ubiquitin-mediated
degradation of DDR/HRR
proteins

Typically combination therapy in multiple
myeloma as well as multiple solid tumor types

* www.clinicaltrials.gov

and other tyrosine kinases, was able to sensitize BCR/
ABL expressing myeloid cells to cisplatin and CLL
lymphocytes to chorambucil. 320,321 Of note, imatinib
was also effective in epithelial cell lines (bladder and
prostate cancer), in terms of sensitizing these cells to
mitomycin C. 322 Lastly, imatinib radiosensitized several
tumor cell lines, and this was correlated with reduced
HRR activities. 322,323

Yamashita and colleagues reported that HSP90 interacts
with FANCA, and HSP90 inhibition disrupts the FA
nuclear core complex, impairs FANCD2 activation, and
causes cisplatin and mitomycin C sensitivity in a FA-
dependent manner. 325 HSP90 may have several radio-
modulating effects (reviewed in 326 ), with disruption of
HRR due to decreased expression of BRCA1 and
RAD51 being one of them. 327

HSP90 Inhibition
The HSP90 chaperone and its associated machinery
mediate the conformational maturation of several fami-
lies of hormone receptors, transcription factors, and
protein kinases (reviewed in 324 ). HSP90 inhibition
prevents its association with client proteins, resulting
in unfolded targets subsequently undergoing ubiqui-
tin-mediated proteasomal degradation. HSP90 0 s client
list was recently expanded to HRR-associated proteins.

Proteasome Inhibition
The majority of intracellular proteins are proteolyzed
by the ubiquitine proteasome. In most cultured mamma-
lian cells, ubiquitin-proteasome dependent-degradation
accounts for 80 e 90% of protein breakdown. 328,329 The
proteasome is recruited to DSBs in yeast and to chro-
matin in mammalian cells, suggesting a direct role for
the proteasome inDSB repair. 330,331 It was found that pro-
teasome function was required for mono-ubiquitination