Title:Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions
Volume: 24
Issue: 15
Author(s): Spyridon P. Basourakos, Likun Li, Ana M. Aparicio, Paul G. Corn, Jeri Kim and Timothy C. Thompson*
Affiliation:
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030- 4009,United States
Keywords:
Platinum-based agents, DDR targeting agents, PARP, WEE-1, ATR, Chk-1/Chk-2.
Abstract: Maintenance of genomic stability is a critical determinant of cell survival and is
necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL)
agents, including platinum-based agents, are first-line chemotherapy treatment for many solid
human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the
damage burden is high and lesions cannot be repaired, malignant cells are unable to divide
and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities
of ICL agents, in particular platinum-based therapies, establish a “molecular landscape,”
i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with
DDR-targeting agents. If the molecular landscape created by platinum-based agents could be
better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed
for the use of DDR-targeting therapies in combination/maintenance protocols for specific,
clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase
(PARP) inhibitors are examples of DDR-targeting therapies that could potentially
increase the DNA damage and replication stress imposed by platinum-based agents in tumor
cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies
have shown that the use of PARP inhibitors together with platinum-based agents is a promising
therapy strategy for ovarian cancer patients with ”BRCAness”, i.e., a phenotypic characteristic
of tumors that not only can involve loss-of-function mutations in either BRCA1 or
BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis
of these promising results, additional mechanism-based studies focused on the use of various
DDR-targeting therapies in combination with platinum-based agents should be considered.
This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that
establish a molecular landscape that can be further exploited therapeutically; (2) multiple
points of potential intervention after ICL agent–induced crosslinking that further predispose to
cell death and can be incorporated into a systematic, therapeutic rationale for combination/
maintenance therapy using DDR-targeting agents; and (3) available agents that can be
considered for use in combination/maintenance clinical protocols with platinum-based agents
for patients with advanced malignancies.
