Abstract
Over the past two decades, elucidation of the genetic defects that underlie cancer has resulted in a plethora of novel targeted cancer drugs. Although these agents can initially be highly effective, resistance to single-agent therapies remains a major challenge. Combining drugs can help avoid resistance, but the number of possible drug combinations vastly exceeds what can be tested clinically, both financially and in terms of patient availability. Rational drug combinations based on a deep understanding of the underlying molecular mechanisms associated with therapy resistance are potentially powerful in the treatment of cancer. Here, we discuss the mechanisms of resistance to targeted therapies and how effective drug combinations can be identified to combat resistance. The challenges in clinically developing these combinations and future perspectives are considered.
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Acknowledgements
The authors thank the members of the Bernards laboratory and P. Borst for discussions. This research of the authors was supported by grant 787925 from the European Research Council (R.B.) and 19-051-ASP from The Mark Foundation (R.B.), the National Natural Science Foundation of China (NSFC82222047 and NSFC82073039) and the Program of Shanghai Academic/Technology Research Leader (22XD1423100) (H.J.).
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R.B. is founder and shareholder of Oncosence. R.B. and L.W. are part-time employees of Oncosence. R.B. is a member of the board of directors of Lixte Biotechnology Holdings. H.J. declares no competing interests.
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Clinical trials listed on the US trial registry site ClinicalTrials.gov involving PD1, PDL1 or CTLA4: https://clinicaltrials.gov/ct2/results?cond=&term=PD-1+OR+PD-L1+OR+CTLA4&cntry=&state=&city=&dist
List of 2018 medicines in development for cancer: https://phrma.org/resource-center/Topics/Medicines-in-Development/List-of-2018-Medicines-in-Development-for-Cancer
Project Optimus: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
Glossary
- Cancer stem cell
-
(CSC). A cell from a small subpopulation of cells within tumours with capabilities of self-renewal, differentiation and tumorigenicity when transplanted into an animal host. Numerous cell surface markers such as CD44, CD24 and CD133 are often used to identify CSCs.
- Collateral lethality
-
A molecular targeted therapeutic strategy, which takes advantage of ‘passenger’ co-deleted genes as points of selective vulnerability.
- Drug holiday
-
An intentional pause in medication for a patient with cancer over a period of time.
- Drug-tolerant persister cells
-
(DTPs). A subpopulation of cancer cells that play a critical role in the development of drug resistance. Persisters can maintain viability under therapy but are typically slowly cycling or dormant. DTPs can re-enter the cell cycle upon drug withdrawal.
- Immune checkpoint blockade
-
(ICB). A type of drug that blocks proteins called checkpoints that are made by some types of immune system cells and some cancer cells. These checkpoints inhibit immune responses, and hence their blockade can activate an immune response against a cancer.
- Microsatellite instability
-
(MSI). The condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair.
- Mitogen-activated protein kinase
-
(MAPK). A cascade of signalling kinases that often originates from receptor tyrosine kinases (RTKs). The MAPK pathway loosely refers to the cascade involving signal transduction through RAS–RAF–MEK and ERK to stimulate cell division.
- Myeloid-derived suppressor cell
-
(MDSC). A myeloid cell that specifically inhibits killing of cells by nature killer cells and CD8+ T cells.
- Oncogene addiction
-
A process in which cancers become dependent on one or several mutated genes for survival.
- Patient-derived xenograft
-
Tumour tissue that has been taken from a patient and implanted into immunodeficient mice. Cancer drugs and other types of treatment may be tested on patient-derived xenografts to see how well they work before they are given to the patient.
- Regulatory T cells
-
(Treg cells). A subpopulation of T cells that suppress effector T cells.
- Synthetic lethality
-
A type of genetic or drug interaction where only the combination of two events results in cell death.
- Truncal mutations
-
Genetic mutations that are present at the trunk of the cancer evolutionary tree. Truncal mutations are present in substantially all cancer cells from a tumour and, therefore, represent a good target for therapy.
- Tumour microenvironment
-
(TME). The microcosm of the tumour, including the non-cancer cells that are part of the tumour, such as the surrounding blood vessels, immune cells, fibroblasts, signalling molecules and the extracellular matrix.
- Tumour mutation burden
-
(TMB). The approximate number of mutations that occurs in the genome of a cancer cell.
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Jin, H., Wang, L. & Bernards, R. Rational combinations of targeted cancer therapies: background, advances and challenges. Nat Rev Drug Discov 22, 213–234 (2023). https://doi.org/10.1038/s41573-022-00615-z
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DOI: https://doi.org/10.1038/s41573-022-00615-z
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