JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma

Abstract

A prominent mechanism of acquired resistance to BRAF inhibitors in BRAFV600-mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change—characterized by a slow-cycling, persistent state. The early persistent state is distinct from the late proliferative, resistant state. However, both differentiation states share common signaling alterations including JUN upregulation. Motivated by the similarities, we found that co-targeting of BRAF and JUN is synergistic in killing fully resistant cells; and when used up-front, co-targeting substantially impairs the formation of the persistent subpopulation. We confirmed that JUN upregulation is a common response to BRAF inhibitor treatment in clinically treated patient tumors. Our findings demonstrate that events shared between early- and late-adaptation states provide candidate up-front co-treatment targets.

Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance

“…The drug‐tolerant state is driven by increased expression of MITF and c‐JUN and is characterized by a mesenchymal phenotype . Our data demonstrate that the combination of PLX4720 and palbociclib induces either cell death or senescence in the majority of cells, clearly indicating that the combination overcomes the PLX4720 induced mesenchymal phenotype.…”

“…Resistance to BRAF inhibitors is associated with an initial reversible nonmutational drug‐tolerant state that leads to the emergence of mutated permanently resistant clones . We have previously demonstrated that treatment of melanoma cell lines for 3 weeks with PLX4720 leads to this drug‐tolerant state .…”

“…Furthermore, in patients who have developed resistance to BRAF inhibitors when given as monotherapy, subsequent treatment with either a MEK inhibitor or a combination of BRAF and MEK inhibitors is also ineffective in most cases . During the early phase of BRAF or MEK inhibitor treatment, rewiring of melanoma cell signaling networks occurs leading to an initial drug‐tolerant state that is reversible and not due to acquired mutations . With continued drug pressure, this reversible drug‐tolerant state eventually develops into nonreversible acquired drug resistance, potentially via the outgrowth of mutated melanoma cells that have acquired novel mutations or cells that were inherently resistant .…”

Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress

“…Together, these observations support that dedifferentiation and MAPK-reactivation routes of BRAF resistance are not mutually exclusive. In some cases, dedifferentiation can be a transient response of adaptive resistance (Fallahi - Sichani et al, 2017; Sun et al, 2014; Titz et al, 2016), and provide a reservoir of cells allowing for expansion or evolution of resistant clones with genetic mechanisms that enable return to the parental differentiation state (Ramirez et al, 2016). In alternate cases, the dedifferentiation state can be stabilized, such as through loss of SOX10 by epigenetic reprogramming (Shaffer et al, 2017).…”

Bad company: Microenvironmentally mediated resistance to targeted therapy in melanoma

“…Such networks of signaling pathways are complex and stochastic in nature, and recent efforts in identifying key players are starting to emerge in the literature. JUN and a protein kinase C (PKC) isoform were recently identified as main drivers of BRAFi resistance (Titz et al, ), whereas p‐21‐activated kinase (PAK) was found to be pivotal in resistance to combinatory MEKi and BRAFi therapy (Zhang et al, ). These studies reveal important insights into the biology of melanoma, and cell‐intrinsic mechanisms of therapy resistance.…”