MEK-Independent Survival of B-RAFV600E Melanoma Cells Selected for Resistance to Apoptosis Induced by the RAF Inhibitor PLX4720

Jiang, Chen Chen; Lai, Fritz; Thorne, Rick F.; Yang, Fan; Líu, Hao; Hersey, Peter; Zhang, Xu Dong

doi:10.1158/1078-0432.ccr-10-2225

Cited by 105 publications

(104 citation statements)

References 36 publications

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“…Jiang and colleagues (36) reported that activation of the PI3K/AKT pathway accounts for, at least in part, the MEK-independent survival of the BRAFi-resistant melanoma cells. The increased PI3K/ AKT activation is the result of extracellular stimuli in some cases.…”

Section: Discussionmentioning

confidence: 99%

The Activation of MAPK in Melanoma Cells Resistant to BRAF Inhibition Promotes PD-L1 Expression That Is Reversible by MEK and PI3K Inhibition

Jiang

Zhou

Giobbie‐Hurder

et al. 2013

Clinical Cancer Research

419

337

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Purpose: Selective BRAF inhibition (BRAFi) provides a paradigm shift for melanoma treatment. The duration of benefit is typically limited before resistance develops. Interest remains in combining targeted and immune therapies to overcome resistance and improve durability of clinical benefit. One mechanism of evading immune destruction is programmed death-1-ligand 1 (PD-L1) expression by tumors that results in potent antitumor immune suppression.Experimental Design: BRAFi-resistant melanoma cells were examined for changes in PD-L1 expression by immunoblot and flow cytometry. Signaling pathways involved in altering PD-L1 expression were examined. Strategies to maximize the effect of the BRAFi therapy were studied including MEKi, MEKi combinations, and additional pathways including phosphoinositide-3 kinase (PI3K).Results: Melanoma cells resistant to BRAFi exhibit increased MAPK signaling and promotion of PD-L1 expression. PD-L1 expression is transcriptionally modulated by c-Jun and augmented by STAT3. MEK inhibition (MEKi) regains downregulation of MAPK signaling and suppresses the production of PD-L1. MEKi in melanoma cells shows dual therapeutic effects with simultaneous suppression of PD-L1 expression and induction of apoptosis. By combining MEKi with BRAFi, an additive effect on the inhibition of PD-L1 expression results.Conclusions: We report a novel mechanism that suppresses preexisting immune responses in patients with melanoma receiving BRAFi therapy. BRAFi resistance leads to increased expression of PD-L1 in melanoma cells, mediated by c-Jun and STAT3. MEKi may be feasible to counteract BRAFi resistance of MAPK reactivation and also for the additive effect of PD-L1 suppression. Potential therapeutic benefits of combining targeted inhibitors and immune modulation to improve patient outcomes should be investigated.

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Section: Discussionmentioning

confidence: 99%

The Activation of MAPK in Melanoma Cells Resistant to BRAF Inhibition Promotes PD-L1 Expression That Is Reversible by MEK and PI3K Inhibition

Jiang

Zhou

Giobbie‐Hurder

et al. 2013

Clinical Cancer Research

419

337

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“…BRAFi-resistant melanoma cells often exhibit crossresistance to other BRAF/MAPK pathway inhibitors such as drugs targeting MEK (44,59,60), suggesting that aberrant activity of other signaling pathways and cellular processes can compensate for the loss of BRAF/MAPK signaling. Indeed, many studies have observed increased activity of key mitogenic signaling proteins such as RTKs and AKT in BRAFi-resistant melanomas (9,14,15,47), while other studies report that BRAFi-resistant melanoma cells inactivate apoptotic pathways through downregulation of BIM (16) and upregulation of MDM4, a negative regulator of TP53 (18).…”

Section: Discussionmentioning

confidence: 99%

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

et al. 2014

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About half of all melanomas harbor a mutation that results in a constitutively active BRAF kinase mutant (BRAF V600E/K ) that can be selectively inhibited by targeted BRAF inhibitors (BRAFis). While patients treated with BRAFis initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. Here, we observed marked elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein were also elevated in BRAFiresistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction of endogenous WNT5A in melanoma decreased cell growth, increased apoptosis in response to BRAFi challenge, and decreased the activity of prosurvival AKT signaling. Conversely, overexpression of WNT5A promoted melanoma growth, tumorigenesis, and activation of AKT signaling. Similarly to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibited growth, sensitized melanoma cells to BRAFi, and reduced AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which promotes AKT signaling through FZD7 and RYK, leading to increased growth and therapeutic resistance. Furthermore, increased WNT5A expression in BRAFi-resistant melanomas correlates with a specific transcriptional signature, which identifies potential therapeutic targets to reduce clinical BRAFi resistance.

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“…A previous report showed that BRAF mutant colorectal cancer COLO206F cells with acquired resistance to the AZD-6244 MEK inhibitor (COLO206F-AR) displayed 10 to 15 copies of mutant BRAF (8). We treated COLO206F parental and COLO206F-AR MEK-resistant cells with the 2 MEK inhibitors, the ERK inhibitor and the BRAF inhibitor PLX4720 (34). We found that, in contrast to MEK and BRAF inhibitors, the ERK inhibitor again largely maintained its ability to block proliferation and pathway suppression at the level of pRSK in the BRAF-amplified COLO206F-AR cells, with only an approximately 4-fold shift in sensitivity to ERKi relative to parental cells compared with a 125- to 150-fold shift in sensitivity to the 2 MEK inhibitors ( Fig.…”

Section: Meki-1 Erkimentioning

confidence: 99%

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

Hatzivassiliou¹,

Liu²,

O’Brien³

et al. 2012

Molecular Cancer Therapeutics

192

155

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The RAS/RAF/MEK pathway is activated in more than 30% of human cancers, most commonly via mutation in the K-ras oncogene and also via mutations in BRAF. Several allosteric mitogen-activated protein/ extracellular signal-regulated kinase (MEK) inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in clinical development. However, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples. To identify strategies to overcome this resistance, we have derived three independent MEK inhibitor-resistant cell lines. Resistance to allosteric MEK inhibitors in these cell lines was consistently linked to acquired mutations in the allosteric binding pocket of MEK. In one cell line, concurrent amplification of mutant K-ras was observed in conjunction with MEK allosteric pocket mutations. Clonal analysis showed that both resistance mechanisms occur in the same cell and contribute to enhanced resistance. Importantly, in all cases the MEK-resistant cell lines retained their addiction to the mitogenactivated protein kinase (MAPK) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERK1/2 kinases. These data suggest that tumors with acquired MEK inhibitor resistance remain dependent on the MAPK pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEK target. Importantly, we show that dual inhibition of MEK and ERK by small molecule inhibitors was synergistic and acted to both inhibit the emergence of resistance, as well as to overcome acquired resistance to MEK inhibitors. Therefore, our data provide a rationale for cotargeting multiple nodes within the MAPK signaling cascade in K-ras mutant tumors to maximize therapeutic benefit for patients.

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MEK-Independent Survival of B-RAFV600E Melanoma Cells Selected for Resistance to Apoptosis Induced by the RAF Inhibitor PLX4720

Cited by 105 publications

References 36 publications

The Activation of MAPK in Melanoma Cells Resistant to BRAF Inhibition Promotes PD-L1 Expression That Is Reversible by MEK and PI3K Inhibition

The Activation of MAPK in Melanoma Cells Resistant to BRAF Inhibition Promotes PD-L1 Expression That Is Reversible by MEK and PI3K Inhibition

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

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