Title | Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Hong A, Moriceau G, Sun L, Lomeli S, Piva M, Damoiseaux R, Holmen SL, Sharpless NE, Hugo W, Lo RS |
Journal | Cancer Discov |
Volume | 8 |
Issue | 1 |
Pagination | 74-93 |
Date Published | 2018 Jan |
ISSN | 2159-8290 |
Abstract | Melanoma resistant to MAPK inhibitors (MAPKi) displays loss of fitness upon experimental MAPKi withdrawal and, clinically, may be resensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi addiction in MAPKi-resistant or melanoma. MAPKi-addiction phenotypes evident upon drug withdrawal spanned transient cell-cycle slowdown to cell-death responses, the latter of which required a robust phosphorylated ERK (pERK) rebound. Generally, drug withdrawal-induced pERK rebound upregulated p38-FRA1-JUNB-CDKN1A and downregulated proliferation, but only a robust pERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi addiction across the board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos-related cell death. Specifically in MEKi-resistant or atypical melanoma, treatment with a type I RAF inhibitor intensified pERK rebound elicited by MEKi withdrawal, thereby promoting a cell death-predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi addiction. Discontinuing targeted therapy may select against drug-resistant tumor clones, but drug-addiction mechanisms are ill-defined. Using melanoma resistant to but withdrawn from MAPKi, we defined a synthetic lethality between supraphysiologic levels of pERK and DNA damage. Actively promoting this synthetic lethality could rationalize sequential/rotational regimens that address evolving vulnerabilities. . |
DOI | 10.1158/2159-8290.CD-17-0682 |
Alternate Journal | Cancer Discov |
PubMed ID | 28923912 |
Grant List | P30 CA016042 / CA / NCI NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:12pm