A possible ‘guide’ for therapy from cancer-associated fibroblasts

Evaluating cancer-associated fibroblasts (CAFs) to understand the patients’ clinical response to targeted therapies and choose them accordingly: this is the hypothesis from a recent study published on Cancer Cell, which identified three different subtypes of fibroblasts with different functional properties, associated with different responses to therapies.

The authors analyzed a wide variety of fibroblasts extracted from biopsies of patients with non-small cell lung cancer; they established a living biobank of patient-derived heterogeneous CAFs to evaluate the functional differences and the response to patient-matched therapies. The study identified three different types of CAF: fibroblasts that abundantly express hepatocyte growth factor (HGF) and fibroblast growth factor 7 (FGF7) and responsive to tyrosine kinase inhibitor therapies, those who express mainly FGF7 and have a moderately protective profile, those who do not express either factor and were more resistant to treatment.

The functional differences between fibroblasts are indeed associated with differences in the tumor immune microenvironment and in clinical response to targeted therapies. Oncogenic mutations in epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK) fusions are present in about 20% and 5%, respectively, of advanced NSCLC, and tyrosine kinase inhibitors constitute the standard-of-care of patients. However, patients whose tumors carrying the same genetic alteration do not benefit equally from the same treatment: only a few achieve complete response whereas the majority of patients show different degrees of response or even no response. The mechanism of resistance to EGFR and ALK tyrosine kinase inhibitors treatments includes HGF and FGF7 and the new study provides substantial evidence supporting that the CAF functional category, identified by their level of expression, determines the overall tyrosine kinase inhibitors response and immune therapy response by modifying the tumor microenvironment: the third CAF subtype, where there’s no expression of HGF and FGF7 and no CAF rescue but a tumor infiltrating lymphocyte status, could benefit more from immunotherapy. «Our approach in exploring and exploiting fibroblast heterogeneity may also provide a valuable paradigm for these disciplines to further improve clinical patient management. Apart from targeted therapy, this CAF classification also has potential for evaluating patients in the context of immune therapy and may also aid in the research in other aspects of cancer biology», authors say.