Tumor expression of CGRP confers sensitivity to growth inhibition by the anti-CGRP antibody fremanezumab.

Calcitonin gene related peptide (CGRP) is a neuropeptide exerting key neuromodulatory, vasoactive and immune functions within the periphery and central nervous system. Drugs targeting CGRP such as anti-CGRP mAbs or small molecule CGRP receptor antagonists have been recently approved for prevention and acute treatment of migraine. A growing body of evidence, however, indicates that CGRP plays key roles in tumor growth. Specifically, the neuropeptide promotes tumor angiogenesis, counteracts antitumor immune responses, and supports cancer proliferation in nutrient-poor environment via autophagic activation. There is general agreement that tumor-infiltrating sensory nerve fibers represent the source of CGRP within neoplasms. In keeping with the tumorigenic role of CGRP, several studies report anticancer effects of rimegepant, a CGRP receptor antagonist. In the present study, by means of in vitro and xenograft models we build upon these findings showing that CGRP can be released within the tumor microenvironment directly by cancer cells. Of note, the migraine preventative anti-CGRP mAb fremanezumab selectively counteracted growth to CGRP-proficient tumors. The antitumoral effect occurred in spite of lack of evidence for intratumoral sensory fiber infiltration, angiogenesis inhibition, or promotion of autophagy. The antibody, however, by altering ERK signaling, might counteract MAPK-dependent growth signaling in CGRP-expressing tumors. Collectively, our findings disclose for the first time the tumorigenic effects of CGRP released from cancer cells and suggest the translational potential of clinically available anti-CGRP monoclonal antibodies as a therapeutic strategy for cancer.