Abstract
The resistance of melanoma to current treatment modalities represents a major obstacle for durable therapeutic response, and thus the elucidation of mechanisms of resistance is urgently needed. The crucial functions of activating transcription factor-2 (ATF2) in the development and therapeutic resistance of melanoma have been previously reported, although the precise underlying mechanisms remain unclear. Here, we report a protein kinase C-ɛ (PKCɛ)- and ATF2-mediated mechanism that facilitates resistance by transcriptionally repressing the expression of interferon-β1 (IFNβ1) and downstream type-I IFN signaling that is otherwise induced upon exposure to chemotherapy. Treatment of early-stage melanomas expressing low levels of PKCɛ with chemotherapies relieves ATF2-mediated transcriptional repression of IFNβ1, resulting in impaired S-phase progression, a senescence-like phenotype and increased cell death. This response is lost in late-stage metastatic melanomas expressing high levels of PKCɛ. Notably, nuclear ATF2 and low expression of IFNβ1 in melanoma tumor samples correlates with poor patient responsiveness to biochemotherapy or neoadjuvant IFN-α2a. Conversely, cytosolic ATF2 and induction of IFNβ1 coincides with therapeutic responsiveness. Collectively, we identify an IFNβ1-dependent, cell-autonomous mechanism that contributes to the therapeutic resistance of melanoma via the PKCɛ–ATF2 regulatory axis.
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References
Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 2014; 508: 118–122.
Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010; 468: 968–972.
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010; 468: 973–977.
Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 2014; 4: 94–109.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–723.
Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517–2526.
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014; 32: 1020–1030.
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369: 134–144.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443–2454.
Ives NJ, Stowe RL, Lorigan P, Wheatley K . Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol 2007; 25: 5426–5434.
Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM . Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 2011; 16: 5–24.
Rubin KM . Management of primary cutaneous and metastatic melanoma. Semin Oncol Nurs 2013; 29: 195–205.
Schuchter LM . Adjuvant interferon therapy for melanoma: high-dose, low-dose, no dose, which dose? J Clin Oncol 2004; 22: 7–10.
Lau E, Kluger H, Varsano T, Lee K, Scheffler I, Rimm DL et al. PKCepsilon promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Cell 2012; 148: 543–555.
Rudalska R, Dauch D, Longerich T, McJunkin K, Wuestefeld T, Kang TW et al. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat Med 2014; 20: 1138–1146.
Bhoumik A, Jones N, Ronai Z . Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity. Proc Natl Acad Sci USA 2004; 101: 4222–4227.
Varsano T, Lau E, Feng Y, Garrido M, Milan L, Heynen-Genel S et al. Inhibition of melanoma growth by small molecules that promote the mitochondrial localization of ATF2. Clin Cancer Res 2013; 19: 2710–2722.
Mirzoeva OK, Petrini JH . DNA replication-dependent nuclear dynamics of the Mre11 complex. Mol Cancer Res 2003; 1: 207–218.
Haferkamp S, Borst A, Adam C, Becker TM, Motschenbacher S, Windhovel S et al. Vemurafenib induces senescence features in melanoma cells. J Invest Dermatol 2013; 133: 1601–1609.
Pencheva N, Buss CG, Posada J, Merghoub T, Tavazoie SF . Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation. Cell 2014; 156: 986–1001.
Koyanagi K, O'Day SJ, Gonzalez R, Lewis K, Robinson WA, Amatruda TT et al. Serial monitoring of circulating melanoma cells during neoadjuvant biochemotherapy for stage III melanoma: outcome prediction in a multicenter trial. J Clin Oncol 2005; 23: 8057–8064.
Koyanagi K, O'Day SJ, Boasberg P, Atkins MB, Wang HJ, Gonzalez R et al. Serial monitoring of circulating tumor cells predicts outcome of induction biochemotherapy plus maintenance biotherapy for metastatic melanoma. Clin Cancer Res 2010; 16: 2402–2408.
Gajewski TF, Fuertes MB, Woo SR . Innate immune sensing of cancer: clues from an identified role for type I IFNs. Cancer Immunol Immunother 2012; 61: 1343–1347.
Jacobs AT, Ignarro LJ . Lipopolysaccharide-induced expression of interferon-beta mediates the timing of inducible nitric-oxide synthase induction in RAW 264.7 macrophages. J Biol Chem 2001; 276: 47950–47957.
Malmgaard L, Salazar-Mather TP, Lewis CA, Biron CA . Promotion of alpha/beta interferon induction during in vivo viral infection through alpha/beta interferon receptor/STAT1 system-dependent and -independent pathways. J Virol 2002; 76: 4520–4525.
Wang J, Basagoudanavar SH, Wang X, Hopewell E, Albrecht R, Garcia-Sastre A et al. NF-kappa B RelA subunit is crucial for early IFN-beta expression and resistance to RNA virus replication. J Immunol 2010; 185: 1720–1729.
Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18: 158–166.
Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET et al. Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer 2006; 106: 375–382.
Testori A, Rutkowski P, Marsden J, Bastholt L, Chiarion-Sileni V, Hauschild A et al. Surgery and radiotherapy in the treatment of cutaneous melanoma. Ann Oncol 2009; 20: vi22–vi29.
Bhoumik A, Takahashi S, Breitweiser W, Shiloh Y, Jones N, Ronai Z . ATM-dependent phosphorylation of ATF2 is required for the DNA damage response. Mol Cell 2005; 18: 577–587.
Eiro N, Bermudez-Fernandez S, Fernandez-Garcia B, Atienza S, Beridze N, Escaf S et al. Analysis of the expression of interleukins, interferon beta, and nuclear factor-kappa B in prostate cancer and their relationship with biochemical recurrence. J Immunother 2014; 37: 366–373.
Snijders AM, Langley S, Mao JH, Bhatnagar S, Bjornstad KA, Rosen CJ et al. An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival. Oncotarget 2014; 5: 4011–4025.
Ryu H, Oh JE, Rhee KJ, Baik SK, Kim J, Kang SJ et al. Adipose tissue-derived mesenchymal stem cells cultured at high density express IFN-beta and suppress the growth of MCF-7 human breast cancer cells. Cancer Lett 2014; 352: 220–227.
Maeda S, Wada H, Naito Y, Nagano H, Simmons S, Kagawa Y et al. Interferon-alpha acts on the S/G2/M phases to induce apoptosis in the G1 phase of an IFNAR2-expressing hepatocellular carcinoma cell line. J Biol Chem 2014; 289: 23786–23795.
Yue C, Xu J, Tan Estioko MD, Kotredes KP, Lopez-Otalora Y, Hilliard BA et al. Host STAT2/type I interferon axis controls tumor growth. Int J Cancer 2014; 136: 117–126.
Acknowledgements
We thank Serge Fuchs (UPENN) and members of the Ronai laboratory for crucial scientific discussions and critical reading of this manuscript. Additional thanks to Mitch Levesque and Valerie Amann for their assistance in providing patient samples from the Department of Dermatology, University of Zurich. We are grateful to Jian-Liang Li of the SBMRI Bioinformatics Core, as well as the SBMRI Flow Cytometry and Histology Core, for technical support. Support from NCI P01 (CA128814), R01 (CA179170), Hervey Family Non-endowment Fund at The San Diego Foundation and a Melanoma Research Foundation grant to ZAR are gratefully acknowledged. Support from NCI Grants R01 (CA164679) and P01 (CA177322) to CW and P50 SPORE (CA121973) to JMK is also gratefully acknowledged. EL has been supported by K99 (CA172705) and T32 (CA121949) Grants.
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Lau, E., Sedy, J., Sander, C. et al. Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy. Oncogene 34, 5739–5748 (2015). https://doi.org/10.1038/onc.2015.22
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DOI: https://doi.org/10.1038/onc.2015.22
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