RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK–positive lung cancer

Hrustanovic, Gorjan; Olivas, Victor; Pazarentzos, Evangelos; Tulpule, Asmin; Asthana, Saurabh; Blakely, Collin M.; Okimoto, Ross A.; Li, Lin; Neel, Dana S.; Sabnis, Amit J.; Flanagan, Jennifer C.; Chan, Elton; Varella‐Garcia, Marileila; Aisner, Dara L.; Vaishnavi, Aria; Ou, Sai Hong Ignatius; Collisson, Eric A.; Ichihara, Eiki; Mack, Philip C.; Lovly, Christine M.; Karachaliou, Niki; Rosell, Rafael; Riess, Jonathan W.; Doebele, Robert C.; Bivona, Trever G.

doi:10.1038/nm.3930

Cited by 246 publications

(252 citation statements)

References 42 publications

(51 reference statements)

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“…Analysis of post-progression biopsy specimens has proven extremely valuable, facilitating a greater understanding of molecular mechanisms of crizotinib resistance (6,7). Broadly speaking, such mechanisms have been classified as involving either on-target genetic alterations (e.g., ALK resistance mutations, ALK gene amplification) or off-target mechanisms of resistance (e.g., up-regulation of bypass signaling pathways, such as EGFR, KIT, IGF-1R, SRC, MEK/ERK and others; ref 6,[8][9][10][11]. In published series to date, on-target resistance mechanisms have been found in approximately one-third of patients progressing on crizotinib (6,7).…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer

Gainor¹,

Dardaei²,

Yoda³

et al. 2016

European Journal of Cancer

163

304

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Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer

Gainor¹,

Dardaei²,

Yoda³

et al. 2016

European Journal of Cancer

163

304

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“…To address this hypothesis, we used an established acquired resistance assay (4,37,38) in representative LA cell lines from our panel that express either V600E or non-V600 mutant forms of BRAF. Using HCC364 (BRAF V600E ) cells, we found that cotreatment with either erlotinib or everolimus (at concentrations that suppress signaling; Fig.…”

Section: Resultsmentioning

confidence: 99%

Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer

Okimoto

Olivas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic activation of protein kinase BRAF drives tumor growth by promoting mitogen-activated protein kinase (MAPK) pathway signaling. Because oncogenic mutations in BRAF occur in ∼2-7% of lung adenocarcinoma (LA), BRAF-mutant LA is the most frequent cause of BRAF-mutant cancer mortality worldwide. Whereas most tumor types harbor predominantly the BRAF V600E -mutant allele, the spectrum of BRAF mutations in LA includes BRAF V600E (∼60% of cases) and non-V600E mutant alleles (∼40% of cases) such as BRAF G469A and BRAF G466V. The presence of BRAF V600E in LA has prompted clinical trials testing selective BRAF inhibitors such as vemurafenib in BRAF V600E -mutant patients. Despite promising clinical efficacy, both innate and acquired resistance often result from reactivation of MAPK pathway signaling, thus limiting durable responses to the current BRAF inhibitors. Further, the optimal therapeutic strategy to block non-V600E BRAF-mutant LA remains unclear. Here, we report the efficacy of the Raf proto-oncogene serine/ threonine protein kinase (RAF) inhibitor, PLX8394, that evades MAPK pathway reactivation in BRAF-mutant LA models. We show that PLX8394 treatment is effective in both BRAF V600E and certain non-V600 LA models, in vitro and in vivo. PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAF V600E that promotes vemurafenib-insensitive MAPK pathway signaling. We further show that acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor. Our study provides a biological rationale and potential polytherapy strategy to aid the deployment of PLX8394 in lung cancer patients.ncogenic mutations in the BRAF serine/threonine protein kinase occur in a wide spectrum of solid tumor malignancies, most notably melanoma, colorectal cancer, and lung adenocarcinoma (1). Mutant BRAF promotes tumor growth by hyperactivating the RAF-MEK-ERK signaling cascade (2-5). BRAF V600E is the most common oncogenic form of BRAF in most tumor types, and selective RAF inhibitors such as vemurafenib and dabrafenib have demonstrated clinical efficacy in melanoma and LA harboring BRAF V600E (6-9). Despite these findings, ∼15% of BRAF mutant cancers do not respond to BRAF inhibitors, and the majority of patients who achieve a response will inevitably acquire resistance to these targeted agents, predominantly through reactivation of MAPK pathway signaling (4, 10-16).The clinical efficacy of RAF inhibitors depends on the degree of suppression of MAPK pathway output (8). Vemurafenib and dabrafenib paradoxically activate the MAPK pathway in cells with oncogenic RAS or increased upstream receptor signaling, thereby enhancing cellular proliferation that can promote cutaneous squamous cell carcinomas and keratoacanthomas that often harbor RAS mutations, and potentially other RAS-driven malignancies (17-25). Combination therapy with a MEK i...

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“…3 We found that RAF-MEK-ERK signaling was uniquely required for ALKC lung cancer cell survival (Fig. 1);.…”

mentioning

confidence: 80%

“…3 ALK inhibitors (crizotinib and ceritinib) are initially, yet but only transiently, effective in some, but not all, ALKC mutant patients because of resistance. 4,5 One promising approach to overcome such resistance is the use of a rational upfront combination therapy targeting an oncogenic protein plus a critical downstream pathway.…”

mentioning

confidence: 99%

“…6 However, which effector pathway is most critical to as a target in cancers with an oncogenic receptor kinase, such as EML4-ALK, is unclear since receptor kinases typically activate multiple pathways. 3 We hypothesized that dissection of the pathway dependencies in ALKC lung cancer cells may reveal the individual pathway that is essential for ALKC lung cancer cell survival and is the critical determinant of ALK inhibitor response.…”

mentioning

confidence: 99%

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RAS-MAPK signaling influences the efficacy of ALK-targeting agents in lung cancer

Hrustanovic

Bivona

2015

Molecular & Cellular Oncology

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RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK–positive lung cancer

Cited by 246 publications

References 42 publications

Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer

Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer

Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer

RAS-MAPK signaling influences the efficacy of ALK-targeting agents in lung cancer

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