Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma

Sun, Chong; Wang, Liqin; Huang, Sidong; Heynen, Guus J.J.E.; Prahallad, Anirudh; Robert, Caroline; Haanen, John B.A.G.; Blank, Christian U.; Wesseling, Jelle; Willems, Stefan M.; Zecchin, Davide; Hobor, Sebastijan; Bajpe, Prashanth Kumar; Lieftink, Cor; Mateus, C.; Vagner, Stéphan; Grernrum, Wipawadee; Hofland, Ingrid; Schlicker, Andreas; Wessels, Lodewyk F.A.; Beijersbergen, Roderick L.; Bardelli, Alberto; Nicolantonio, Federica Di; Eggermont, Alexander M.M.; Bernards, René

doi:10.1038/nature13121

Cited by 753 publications

(826 citation statements)

References 28 publications

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“…Chmielecki and colleagues ( 78 ) demonstrated that erlotinib-resistant NSCLC cells grew more slowly than their sensitive counterparts, and, interestingly, resistance was not maintained in the absence of the drug. A similar phenomenon has been described for BRAF -mutant melanoma cells, which become resistant to vemurafenib through expression of EGFR ( 79 ).…”

Section: Reviewmentioning

confidence: 79%

Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution

et al. 2014

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The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS , NRAS, and BRAF and amplification of ERBB2 and MET drive primary ( de novo ) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy.Signifi cance: Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their effi cacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted.

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Section: Reviewmentioning

confidence: 79%

Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution

et al. 2014

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“…Alternatively, models can be developed from pretreatment tumour samples, and resistance can be recapitulated in the PDX Although PDXs generally retain drug-sensitivity profiles that are similar to those of the corresponding patient tumour 30,38,62,63 , PDX models derived from treatment-resistant tumours can become sensitive again upon xenografting, owing to the effect of the so-called "drug holiday" in which treatment is discontinued after tumour implantation to facilitate engraftment. Some 13 resistance mechanisms are thus reversible in the absence of drug, as shown for melanoma 64,65 and lung adenocarcinoma 66 . This suggests that treatmentresistant PDXs should be exposed to continuous treatment immediately after implantation, although this is a cost-and labour-intensive approach.…”

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confidence: 98%

Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

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Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the 6 perspective of EurOPDX, an international initiative devoted to PDX-based research.Response to anticancer therapies varies owing to the substantial molecular heterogeneity of human tumours and to poorly defined mechanisms of drug efficacy and resistance 1 . Immortalized cancer cell lines, either cultured in vitro or grown as xenografts, cannot interrogate the complexity of human tumours, and only provide determinate insights into human disease, as they are limited in number and diversity, and have been cultured on plastic over decades 2 .This disconnection in scale and biological accuracy contributes considerably to attrition in drug development [3][4][5] .Surgically derived clinical tumour samples that are implanted in mice (known as patient-derived xenografts (PDXs)) are expected to better inform therapeutic development strategies. As intact tissue -in which the tumour architecture and the relative proportion of cancer cells and stromal cells are both maintained -is directly implanted into recipient animals, the alignment with human disease is enhanced. More importantly, PDXs retain the idiosyncratic characteristics of different tumours from different patients; hence, they can effectively recapitulate the intra-tumour and inter-tumour heterogeneity that typifies human cancer 6-9 . 7 Exhaustive information on the key characteristics and the practical applications of PDXs can be found in recent reviews [10][11][12][13] . In this Opinion article, we discuss basic methodological concepts, as well as challenges and opportunities in developing "next-generation" models to improve the reach of PDXs as preclinical tools for in vivo studies (TABLE 1). We also elaborate on the merits of PDXs for exploring the intrinsic heterogeneity and subclonal genetic evolution of individual tumours, and discuss how this may influence therapeutic resistance. Finally, we examine the utility of PDXs in navigating complex variables in clinical decision-making, such as the discovery of predictive and prognostic biomarkers, and the categorization of genotype-drug response correlations in high-throughput formats. Being primarily co-authored by leading members of the EurOPDX Consortium (see Further information), we provide...

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“…Similarly, knockdown of the transcription factor SOX10 in melanoma cell lines induces BRAF inhibitor resistance by induction of TβRII and TGF-β signaling, ultimately resulting in increased receptor tyrosine kinase expression (45). In both of these contexts, TGF-β-induced resistance to targeted therapies is associated with enhanced signaling through the ERK MAP kinase pathway.…”

Section: Discussionmentioning

confidence: 99%

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanisms

Shi

Mihaylova

Kuruvilla

et al. 2016

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

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Bromodomain and extraterminal domain protein inhibitors (BETi) hold great promise as a novel class of cancer therapeutics. Because acquired resistance typically limits durable responses to targeted therapies, it is important to understand mechanisms by which tumor cells adapt to BETi. Here, through pooled shRNA screening of colorectal cancer cells, we identified tripartite motif-containing protein 33 (TRIM33) as a factor promoting sensitivity to BETi. We demonstrate that loss of TRIM33 reprograms cancer cells to a more resistant state through at least two mechanisms. TRIM33 silencing attenuates down-regulation of MYC in response to BETi. Moreover, loss of TRIM33 enhances TGF-β receptor expression and signaling, and blocking TGF-β receptor activity potentiates the antiproliferative effect of BETi. These results describe a mechanism for BETi resistance and suggest that combining inhibition of TGF-β signaling with BET bromodomain inhibition may offer new therapeutic benefits.bromodomain inhibitor | TRIM33 | JQ1 | drug resistance | TGF-β

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Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma

Cited by 753 publications

References 28 publications

Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution

Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanisms

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