Bête Noire of Chemotherapy and Targeted Therapy: CAF-Mediated Resistance

Simple Summary Tumor cells struggle to survive following treatment. The struggle ends in either of two ways. The drug combination used for the treatment blocks the proliferation of tumor cells and initiates apoptosis of cells, which is a win for the patient, or tumor cells resist the effect of the drug combination used for the treatment and continue to evade the effect of anti-tumor drugs, which is a bête noire of therapy. Cancer-associated fibroblasts are the most abundant non-transformed element of the microenvironment in solid tumors. Tumor cells play a direct role in establishing the cancer-associated fibroblasts’ population in its microenvironment. Since cancer-associated fibroblasts are activated by tumor cells, cancer-associated fibroblasts show unconditional servitude to tumor cells in their effort to resist treatment. Thus, cancer-associated fibroblasts, as the critical or indispensable component of resistance to the treatment, are one of the most logical targets within tumors that eventually progress despite therapy. We evaluate the participatory role of cancer-associated fibroblasts in the development of drug resistance in solid tumors. In the future, we will establish the specific mode of action of cancer-associated fibroblasts in solid tumors, paving the way for cancer-associated-fibroblast-inclusive personalized therapy. Abstract In tumor cells’ struggle for survival following therapy, they resist treatment. Resistance to therapy is the outcome of well-planned, highly efficient adaptive strategies initiated and utilized by these transformed tumor cells. Cancer cells undergo several reprogramming events towards adapting this opportunistic behavior, leading them to gain specific survival advantages. The strategy involves changes within the transformed tumors cells as well as in their neighboring non-transformed extra-tumoral support system, the tumor microenvironment (TME). Cancer-Associated Fibroblasts (CAFs) are one of the components of the TME that is used by tumor cells to achieve resistance to therapy. CAFs are diverse in origin and are the most abundant non-transformed element of the microenvironment in solid tumors. Cells of an established tumor initially play a direct role in the establishment of the CAF population for its own microenvironment. Like their origin, CAFs are also diverse in their functions in catering to the pro-tumor microenvironment. Once instituted, CAFs interact in unison with both tumor cells and all other components of the TME towards the progression of the disease and the worst outcome. One of the many functions of CAFs in influencing the outcome of the disease is their participation in the development of resistance to treatment. CAFs resist therapy in solid tumors. A tumor–CAF relationship is initiated by tumor cells to exploit host stroma in favor of tumor progression. CAFs in concert with tumor cells and other components of the TME are abettors of resistance to treatment. Thus, this liaison between CAFs and tumor cells is a bête noire of therapy. Here, we portray a comprehensive picture of the modes and functions of CAFs in conjunction with their role in orchestrating the development of resistance to different chemotherapies and targeted therapies in solid tumors. We investigate the various functions of CAFs in various solid tumors in light of their dialogue with tumor cells and the two components of the TME, the immune component, and the vascular component. Acknowledgment of the irrefutable role of CAFs in the development of treatment resistance will impact our future strategies and ability to design improved therapies inclusive of CAFs. Finally, we discuss the future implications of this understanding from a therapeutic standpoint and in light of currently ongoing and completed CAF-based NIH clinical trials.