Posted May 28, 2021

Aayoung Hong, Ph.D., University of California, Los Angeles

A paradigm shift for the treatment of aggressive melanoma occurred with the emergence of combined BRAF plus MEK inhibitors (BRAFi+MEKi); however, acquired resistance to these mitogen-activated protein kinase (MAPK) inhibitors (MAPKi) limits long-term patient survival, and therefore remains an urgent clinical problem. Previous research revealed that melanomas with acquired resistance to BRAFi+MEKi became dependent on the presence of these inhibitors for survival (a process termed “drug-addiction”), and that the extent of drug-addiction increased with adaptation to BRAFi+MEKi.¹ Acute withdrawal of these drugs correlates with a strong induction of the MAPK pathway, resulting in stress and ultimately cell death. Rebound levels of phospho-extracellular signal-regulated kinase (p-ERK), a member of the MAPK family, seemed critical for this phenotype because blocking this p-ERK rebound reversed drug-addiction.¹ However, the mechanism by which p-ERK rebound mediates drug-addiction is unknown. Understanding the mechanisms of drug-addiction is essential for elucidating melanoma vulnerabilities and providing diagnostic tools for predicting which patients could benefit from discontinuing targeted therapy. With a Fiscal Year 2015 Peer Reviewed Cancer Research Program Horizon Award, Dr. Aayoung Hong sought to investigate the cellular responses to drug withdrawal in MAPKi-resistant melanoma and to identify therapeutic approaches for enhanced sequential/rotational therapy.

As described in Cancer Discovery, Dr. Hong began the study by investigating the response of BRAF ^V600-mutant, double-drug resistant, and NRAS ^Q61-mutant, MEKi resistant melanoma cell lines to MAPKi withdrawal to assess the variations in the MAPKi-addiction phenotype. Results from these studies demonstrated drug-addiction phenotypes that were characterized by slow-cycling versus cell-death responses. The group then assessed the extent to which p-ERK rebound, caused by MAPKi withdrawal, may be related to the slow-cycling or cell-death responses. They showed that strong and excessive ERK rebound induced both DNA damage and apoptosis-inducing factor (AIF)-mediated death within the cell-death predominant MAPKi-addiction phenotype. On the other hand, weaker levels of p-ERK rebound induced by MAPKi withdrawal only demonstrated cell-cycle slow-down, leading to persistent cells that continued to grow. One of the most significant discoveries demonstrated that, upon MAPKi withdrawal, a slight increase in p-ERK rebound coupled with compromised DNA damage repair was able to change a slow-cycling response into a cell-death response. In vivo experiments with a MEKi-resistant NRAS^MUT patient-derived xenograft model (PDX) as well as a MEKi-resistant non-BRAF V600 or atypical BRAF mutant PDX models were used to validate these strategies to enhance intermittent drug therapy regimens. Results from these studies demonstrated that treatment of MEKi-resistant melanoma cells with vemurafenib, a type I RAF inhibitor, induced tumor regression by promoting a cell-death predominant MAPKi-addiction phenotype by intensifying MEKi-withdrawal-mediated p-ERK rebound. Thus, pharmacologically augmenting both ERK rebound and DNA damage maximized regression of MEKi-resistant melanoma tumors. Dr. Hong’s work, therefore, highlights a potential benefit in coupling strategies for augmenting MAPKi-addiction during periods of intermittent therapy with MAPKi.

Overall, Dr. Hong’s research provides a better understanding of the mechanisms of MAPKi-addiction and highlights the importance of further investigations into potential therapeutic options for controlling MAPKi resistance. This work has the translational potential of using combination therapy in order to overcome relapse as well as developing diagnostic tools for predicting which patients will benefit from intermittent therapy for melanoma. Future studies should further explore the mechanisms by which ERK and DNA damage facilitate pathways of cell-death to guide the discovery of adaptive therapies for evolving melanoma vulnerabilities.

Publication:

Hong A, Moriceau G, Sun L, et al. 2018. Exploiting drug addiction mechanisms to select against MAPKi-resistant melanoma. Cancer Discovery 8(1):74-93.

Reference:

¹ Moriceau G, Hugo W, Hong A, et al. 2015. Tunable-combinational mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell 27:240-256.

Link:

Public and Technical Abstracts: Melanoma Drug Addiction and Its Therapeutic Implications