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 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 EGFRmediated 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.

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 issue 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.