Molecular Medicine Israel

Cross-Resistance: One Cancer Therapy Can Undermine the Next

Targeted cancer therapy may jeopardize the effectiveness of subsequent immunotherapy by reducing dendritic cell numbers and activation, according to study of mice and patient samples.


argeted therapy and immunotherapy are often employed as a one-two punch to treat certain cancers, but sometimes this approach falls short. In a study published on July 15 in Nature Cancer, researchers found that dendritic cells, cells crucial for activating the immune system during immunotherapy, were less active and less numerous in mouse models of melanoma that had become resistant to targeted therapy, explaining why these tumors were less sensitive to immunotherapy. Stimulating dendritic cells restored the tumors’ response to immunotherapy. 

“This study provides mechanistic insight into a phenomenon that many melanoma experts have observed firsthand in the clinic and that has recently been described in retrospective studies: poor response to immunotherapy following the development of resistance to [targeted] therapy,” Brent Hanks, a medical oncologist at Duke University who was not involved in this study, tells The Scientist in an email“Overall, this is an important contribution to melanoma research that may have implications in the management of other . . . cancers as well.”

Indeed, it was early clinical data that sparked the interest of Anna Obenauf, a cancer researcher at the Research Institute of Molecular Pathology in Vienna, Austria, who led the international team behind the new study. “This is a clinical puzzle in a way, because how can these two different types of therapies be connected to each other, and this resistance to one lead to cross-resistance to the other?” While targeted therapy blocks specific molecular pathways within cancer cells to stop proliferation, immunotherapy works by stimulating immune cells to eradicate tumor cells.  

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