The importance of being CAFs (in cancer resistance to targeted therapies)

Abstract

In the last two decades, clinical oncology has been revolutionized by the advent of targeted drugs. However, the efficacy of these therapies is significantly limited by primary and acquired resistance, that relies not only on cell-autonomous mechanisms but also on tumor microenvironment cues. Cancer-associated fibroblasts (CAFs) are extremely plastic cells of the tumor microenvironment. They not only produce extracellular matrix components that build up the structure of tumor stroma, but they also release growth factors, chemokines, exosomes, and metabolites that affect all tumor properties, including response to drug treatment. The contribution of CAFs to tumor progression has been deeply investigated and reviewed in several works. However, their role in resistance to anticancer therapies, and in particular to molecular therapies, has been largely overlooked. This review specifically dissects the role of CAFs in driving resistance to targeted therapies and discusses novel CAF targeted therapeutic strategies to improve patient survival.

Spatial Transcriptomics in Breast Cancer Reveals Tumour Microenvironment-Driven Drug Responses and Clonal Therapeutic Heterogeneity

“…ECM remodelling can reduce the sensitivity to targeted therapies by i) creating a protective niche that physically impedes the delivery of drugs; ii) mechano-transduction of proliferation or anti-apoptotic signals mediated by integrins or iii) metabolic changes induced in cancer cells due to the internalisation of ECM components. These mechanisms have been observed in breast cancer in vivo and in vitro models, which displayed increased resistance to HER2 and multi-kinase inhibitors [97]. Accordingly, TC1.2 was significantly enriched in ECM stiffness, which may explain the overall low sensitivity of this subcluster to the entire collection of tested drugs.…”

Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer

“…Selective CAF subpopulations possess anti-tumorigenic properties, leading to ineffective therapy [ 280 ]. Most CAF-targeted therapy could be combined with other immunotherapy for successful breast cancer treatment [ 281 ]. Lack of preclinical and clinical data is a limitation affecting CAF-targeted therapy [ 282 ].…”

Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography

“…Also, proline is used to produce collagen, which exhibits tumor-protecting features in the extracellular matrix. PYCR1 is overexpressed in cancer-associated fibroblasts and is a target for cancer therapy to slow production of proline for use in collagen. , Altogether, the available data implicate proline biosynthesis as a potential cancer therapy intervention point, motivating the discovery of PYCR1 inhibitors.…”