Precision oncology in metastatic colorectal cancer — from biology to medicine
Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availabili...
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| Vydáno v: | Nature reviews. Clinical oncology Ročník 18; číslo 8; s. 506 - 525 |
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| Hlavní autoři: | , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
London
Nature Publishing Group UK
01.08.2021
Nature Publishing Group |
| Témata: | |
| ISSN: | 1759-4774, 1759-4782, 1759-4782 |
| On-line přístup: | Získat plný text |
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| Shrnutí: | Remarkable progress has been made in the development of biomarker-driven targeted therapies for patients with multiple cancer types, including melanoma, breast and lung tumours, although precision oncology for patients with colorectal cancer (CRC) continues to lag behind. Nonetheless, the availability of patient-derived CRC models coupled with in vitro and in vivo pharmacological and functional analyses over the past decade has finally led to advances in the field. Gene-specific alterations are not the only determinants that can successfully direct the use of targeted therapy. Indeed, successful inhibition of BRAF or KRAS in metastatic CRCs driven by activating mutations in these genes requires combinations of drugs that inhibit the mutant protein while at the same time restraining adaptive resistance via CRC-specific EGFR-mediated feedback loops. The emerging paradigm is, therefore, that the intrinsic biology of CRC cells must be considered alongside the molecular profiles of individual tumours in order to successfully personalize treatment. In this Review, we outline how preclinical studies based on patient-derived models have informed the design of practice-changing clinical trials. The integration of these experiences into a common framework will reshape the future design of biology-informed clinical trials in this field.
Progress in precision medicine for colorectal cancer continues to lag behind the rapid improvements seen in patients with certain other solid tumour types. Nonetheless, owing largely to the availability of better translational models, novel and effective targeted therapy strategies based on tumour biology are beginning to be developed for subsets of patients. In this Review, the authors summarize these developments and discuss future directions in this rapidly evolving area of research.
Key points
The efficacy of targeted therapies in patients with solid tumours is largely unpredictable owing to intrinsic genetic complexity and a high level of tissue context specificity.
The development of patient-derived models that reflect the genetic heterogeneity of colorectal cancer (CRC) constitutes a successful platform for the development of targeted therapies.
These models have enabled the validation of retrospectively identified biomarkers in clinical trials and the optimization of prospective biomarkers to guide the selection of novel targeted therapies, such as those targeting HER2.
Longitudinal evaluations of the genomic evolution of CRC enabled by analysis of liquid biopsy samples have further increased the understanding of the mechanisms of resistance to targeted agents.
Investigations of resistance to targeted therapies have revealed convergence on CRC-specific feedback loops within the MAPK signalling pathway as a core mechanism of survival.
Co-inhibition with agents targeting EGFR and the specific oncogenic mutation has proved crucial in the clinical development of effective regimens for
BRAF
-mutant CRCs, and has also been demonstrated to be beneficial in the context of
KRAS
G12C
-mutant CRC. |
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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23 |
| ISSN: | 1759-4774 1759-4782 1759-4782 |
| DOI: | 10.1038/s41571-021-00495-z |