Amphiregulin: a Potential Target to Improve Chemotherapy

There is more to a tumour than the cancer cells that compose it. We are increasingly understanding the importance of the tumour microenvironment – the network of blood vessels, non-cancer cells and signalling molecules that surround and affect tumour growth. Of particular interest are the senescence-associated secretory cells: senescent stromal cells surrounding the cancer that release a variety of factors that aid the expansion of the tumour.

This study, published in Aging Cell, suggests that amphiregulin, a growth factor released by senescent cells, plays an important role in promoting resistance to chemotherapy by suppressing the immune system.

There is quite a lot of information to unpack here. The first key finding was that prostate cancer patients produced more amphiregulin following chemotherapy, and higher amphiregulin production was associated with lower survival. Circulating amphiregulin also correlated very closely with other known contributors to the tumour microenvironment, notably IL-8. Thus, measuring amphiregulin could serve as a means to clinically assess the development of the tumour microenvironment. This could aid the development of safer and more effective chemotherapy treatments.

The second, perhaps more exciting finding, was that blocking the actions of amphiregulin improved the response to chemotherapy in mice. It remains to be seen whether this finding will translate to humans, but this research provides a proof of concept that targeting major factors produced by secretory senescent cells could improve cancer treatment outcomes.

Aging is characterized by a progressive loss of physiological integrity, while cancer represents one of the primary pathological factors that severely threaten human lifespan and healthspan. In clinical oncology, drug resistance limits the efficacy of most anticancer treatments, and identification of major mechanisms remains a key to solve this challenging issue. Here, we highlight the multifaceted senescence‐associated secretory phenotype (SASP), which comprises numerous soluble factors including amphiregulin (AREG). Production of AREG is triggered by DNA damage to stromal cells, which passively enter senescence in the tumor microenvironment (TME), a process that remarkably enhances cancer malignancy including acquired resistance mediated by EGFR. Furthermore, paracrine AREG induces programmed cell death 1 ligand (PD‐L1) expression in recipient cancer cells and creates an immunosuppressive TME via immune checkpoint activation against cytotoxic lymphocytes. Targeting AREG not only minimized chemoresistance of cancer cells, but also restored immunocompetency when combined with classical chemotherapy in humanized animals. Our study underscores the potential of in vivo SASP in driving the TME‐mediated drug resistance and shaping an immunosuppressive niche, and provides the proof of principle of targeting major SASP factors to improve therapeutic outcome in cancer medicine, the success of which can substantially reduce aging‐related morbidity and mortality.

Xu, Q., Long, Q., Zhu, D., Fu, D., Zhang, B., & Han, L. et al. (2019). Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD‐L1)‐mediated immunosuppression. Aging Cell, 18(6). doi: 10.1111/acel.13027