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Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.

ABSTRACT: Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1 These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. To identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer. Cancer Res; 76(15); 4504-15. ©2016 AACR.

SUBMITTER: Oddo D

PROVIDER: S-EPMC4970882 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.

Oddo Daniele D Sennott Erin M EM Barault Ludovic L Valtorta Emanuele E Arena Sabrina S Cassingena Andrea A Filiciotto Genny G Marzolla Giulia G Elez Elena E van Geel Robin M J M RM Bartolini Alice A Crisafulli Giovanni G Boscaro Valentina V Godfrey Jason T JT Buscarino Michela M Cancelliere Carlotta C Linnebacher Michael M Corti Giorgio G Truini Mauro M Siravegna Giulia G Grasselli Julieta J Gallicchio Margherita M Bernards René R Schellens Jan H M JH Tabernero Josep J Engelman Jeffrey A JA Sartore-Bianchi Andrea A Bardelli Alberto A Siena Salvatore S Corcoran Ryan B RB Di Nicolantonio Federica F

Cancer research 20160616 15

Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinatio ...[more]

PMID: 27312529

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Project description:Therapies targeting oncogene addiction have had a tremendous impact on tumor growth and patient outcome, but drug resistance continues to be problematic. One approach to deal with the challenge of resistance entails extending anticancer treatments beyond targeting cancer cells by additionally altering the tumor microenvironment. Understanding how the tumor microenvironment contributes to the evolution of diverse resistance pathways could aid in the design of sequential treatments that can elicit and take advantage of a predictable resistance trajectory. Tumor-associated macrophages often support neoplastic growth and are frequently the most abundant immune cell found in tumors. Here, we used clinically relevant in vivo Braf-mutant melanoma models with fluorescent markers to track the stage-specific changes in macrophages under targeted therapy with Braf/Mek inhibitors and assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ monocyte-derived macrophage infiltration rose, suggesting that macrophage influx at this point could facilitate the onset of stable drug resistance that melanoma cells show after several weeks of treatment. Comparison of melanomas that develop in a Ccr2-proficient or -deficient microenvironment demonstrated that lack of melanoma infiltrating Ccr2+ macrophages delayed onset of resistance and shifted melanoma cell evolution towards unstable resistance. Unstable resistance was characterized by sensitivity to targeted therapy when factors from the microenvironment were lost. Importantly, this phenotype was reversed by coculturing melanoma cells with Ccr2+ macrophages. Overall, this study demonstrates that the development of resistance may be directed by altering the tumor microenvironment to improve treatment timing and the probability of relapse.SignificanceCcr2+ melanoma macrophages that are active in tumors during the drug-tolerant persister state following targeted therapy-induced regression are key contributors directing melanoma cell reprogramming toward specific therapeutic resistance trajectories.

Project description:BackgroundCombinatorial inhibition of epidermal growth factor receptor (EGFR) and BRAF shows remarkable clinical benefits in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). However, the tumor may inevitably develop resistance to the targeted therapy, thereby limiting the response rate and durability. This study aimed to determine the genetic alterations associated with intrinsic and acquired resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC.MethodsTargeted sequencing of 520 cancer-related genes was performed in tumor tissues and in plasma samples collected from patients with BRAF V600E-mutant mCRC, who were treated with EGFR/BRAF ± MEK inhibitors, before and after the targeted treatment. Clinical benefit was defined as an objective response or a stable disease lasting longer than the median progression-free survival (PFS).ResultsIn all, 25 patients with BRAF V600E-mutant mCRC were included in this study. Those with RNF43 mutations (n = 8) were more likely to achieve clinical benefit from EGFR/BRAF inhibitors than those with wild-type RNF43 (87.5% versus 37.5%, p = 0.034). Genetic alterations in receptor tyrosine kinase genes (n = 6) were associated with worse PFS (p = 0.005). Among the 23 patients whose disease progressed after the EGFR/BRAF-targeted therapy, at least one acquired resistance-related mutation was detected in 12 patients. Acquired mutations were most frequently observed in the mitogen-activated protein kinase pathway-related genes (n = 9), including KRAS (G12D and Q61H/R), NRAS (Q61L/R/K and amplification), BRAF (amplification), and MEK1 (K57T). MET amplification and PIK3R1 Q579fs mutation emerged in three patients and one patient, respectively, after disease progression.ConclusionMultiple genetic alterations are associated with clinical benefits and resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Our findings provide novel insights into strategies for overcoming resistance to EGFR/BRAF inhibitors in patients with BRAF V600E-mutant mCRC.

Dataset Information

Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.

Publications

Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.

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