Combined inhibition of focal adhesion kinase and RAF/MEK elicits synergistic inhibition of melanoma growth and reduces metastases
Jared Almazan, Tursun Turapov, David A. Kircher, Karly A. Stanley, Katie M. Culver, A. Paulina Medellin, MiKaela N. Field, Gennie L. Parkman, Howard Colman, Sílvia Coma, Jonathan A. Pachter, Sheri L. Holmen
Abstract
This study addresses the urgent need for effective therapies for patients with brain metastases from cutaneous melanoma, a major cause of treatment failure despite recent therapeutic advances. Utilizing mouse models that mimic human melanoma brain metastases, this study investigates the necessity of focal adhesion kinase (FAK) in the development of distant metastases and its potential as a therapeutic target. Pharmacological inhibition of FAK demonstrates significant efficacy in reducing the development of brain metastases in preclinical mouse models. Importantly, the study provides insight into the crosstalk between FAK and mitogen-activated protein kinase (MAPK) pathway signaling and highlights the synergistic effects of combined inhibition of FAK, rapidly accelerated fibrosarcoma (RAF), and mitogen-activated protein kinase kinase (MEK) in cutaneous melanoma. These findings provide the rationale for clinical evaluation of the efficacy of the FAK inhibitor defactinib and the RAF/MEK inhibitor avutometinib in patients with brain metastases from cutaneous melanoma. • FAK/RAF/MEK inhibition synergistically induces apoptosis in melanoma cells in vitro • FAK inhibition directly reduces brain metastasis development in vivo • The combination is well tolerated and promotes tumor regression in vivo • FAK/RAF/MEK inhibition prolongs survival in mice with existing brain metastases Patients with melanoma brain metastases have a poor prognosis and limited treatment options. Here, Almazan et al. demonstrate the synergistic effects of targeting focal adhesion kinase (FAK) and RAF/MEK to inhibit melanoma growth and metastasis. These findings highlight the therapeutic potential of targeting both FAK and RAF/MEK signaling in this disease.