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Novelties in Dermatology
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Available online 15 January 2022
Tirbanibulin: review of its novel mechanism of action and how it fits into the treatment of actinic keratosis
Tirbanibulina: revisión de su mecanismo de acción novedoso y de cómo encaja en el tratamiento de la queratosis actínica
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Y. Gilabertea,
Corresponding author
ygilaberte@salud.aragon.es

Corresponding author.
, M.T. Fernández-Figuerasb,c
a Servicio de Dermatología, Hospital Universitario Miguel Servet, IIS Aragón, Zaragoza, Spain
b Servicio de Anatomía Patológica, Hospital Universitari General de Catalunya, Grupo Quirón Salud, Sant Cugat del Vallès, Barcelona, Spain
c Universitat Internacional de Catalunya, Sant Cugat del Vallès, Barcelona, Spain
Received 07 July 2021. Accepted 18 July 2021
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Table 1. Potency of Tirbanibulin in Various Tumor Cell Lines
Abstract

Actinic keratosis (AK), a skin condition characterized by the proliferation of atypical keratinocytes, can progress to squamous cell carcinoma. Existing treatments are effective but cause high rates of local skin reactions. Tirbanibulin, one of the treatments under development for AK, is a novel synthetic drug with powerful in vitro and in vivo antiproliferative and antitumor effects. Its efficacy in this setting was recently demonstrated in 2 phase 3 clinical trials. We review tirbanibulin’s mechanism of action based on the current literature and several unpublished preclinical studies. We also review treatments available for AK and discuss how tirbanibulin, with its novel mechanism of action, fits into the therapeutic landscape.

Keywords:
Tirbanibulin
Actinic keratosis
Cutaneous squamous cell carcinoma
Mechanism of action
Apoptosis
Adherence
Resumen

La queratosis actínica (QA) es una afección cutánea caracterizada por la proliferación de queratinocitos mutados que pueden convertirse en carcinoma escamoso cutáneo. Las terapias disponibles, aunque efectivas, están asociadas con una alta frecuencia de reacciones cutáneas locales graves. Tirbanibulina, uno de los tratamientos para la QA actualmente en desarrollo, es un nuevo fármaco sintético de origen químico con potentes efectos antiproliferativos y antitumorales in vitro e in vivo con eficacia probada en el tratamiento de la QA, demostrada recientemente en dos ensayos clínicos de fase III. En la presente revisión, se muestra el mecanismo de acción de tirbanibulina en base a la literatura relevante y los resultados de varios estudios preclínicos no publicados. Además, se plantea el escenario actual en cuanto a los tratamientos disponibles y cómo el mecanismo de acción novedoso de tirbanibulina encaja en el tratamiento de la QA.

Palabras clave:
Tirbanibulina
Queratosis actínica
Carcinoma escamoso cutáneo
Mecanismo de acción
Apoptosis
Adherencia
Full Text
Introduction

Actinic keratosis (AK) is a skin condition associated with prolonged exposure to UV light and characterized by the uncontrolled proliferation of mutated keratinocytes that may develop into cutaneous squamous cell carcinoma (cSCC). The main genetic abnormalities include mutations in the tumor suppressor p53 gene, which are crucial for inducing apoptosis in damaged cells1,2.

Tirbanibulin is a new synthetic chemical drug with potent antiproliferative and antitumor effects both in vitro and in vivo3 that has recently demonstrated efficacy in the treatment of AK in 2 phase 3 clinical trials4.

Below, we review the mechanism of action of tirbanibulin, with emphasis on relevant literature and the results of preclinical studies. In addition, we show how this novel mechanism of action fits into the treatment of AK, alongside currently available options.

Inhibition of Tubulin Polymerization

Studies on photoaffinity and in vitro competitive binding with purified tubulin and tubulin binders (colchicine, vincristine, docetaxel) have revealed α and β tubulins to be the primary targets of tirbanibulin.

Tubulin is a structural protein involved in cell migration, protein transport, and cell division. The functional significance of tirbanibulin binding to tubulin lies in the fact that it inhibits tubulin polymerization in a reversible and concentration-dependent manner; the reversibility of the binding also makes the cellular effects reversible, thus explaining the low toxicity of this drug5.

Disruption of the Microtubule Network

Immunofluorescence studies show that tirbanibulin leads to microtubule network disruption in vitro in ovarian cancer cells (RMUS-S and RMUG-L), breast cancer cells (MDA-MB-231), prostate cancer cells (PC3), peripheral blood mononuclear cells (PBMCs), and immortalized keratinocytes (CCD-1106 KERTr)3,5–7. It was also observed that the filamentous tubulin structures were restored when tirbanibulin was removed from the cell culture6.

In vivo, murine models based on various tumor tissues showed that staining patterns were similar to those obtained in vitro with tumor cells compared to those of the control group7,8.

Cell Cycle Arrest

After incubation of CCD-1106 KERTr cells with tirbanibulin and comparison with the same cell line incubated with dimethyl sulfoxide (DMSO) as a control, cell cycle analysis by flow cytometry indicated that tirbanibulin leads to cell cycle arrest at the growth 2 and mitosis (G2/M) interphase (Fig. 1). Similar results were obtained with PBMCs and cell lines from breast, cervical, prostate, liver, and lung cancer3,5,9. At the end of the interphase, the microtubules carry all the genetic material to each pole to complete cell division10. It is at this point that the main effect of tirbanibulin occurs, thus stopping the cell cycle.

Figure 1.

Cell cycle arrest at growth phase 2/mitosis in an immortalized keratinocyte cell line (CCD-1106 KERTr). CCD-1106 KERTr cells were incubated with DMSO or tirbanibulin (50 nM) for 40 hours. They were then permeated and stained with propidium iodide for subsequent analysis using flow cytometry. DMSO indicates dimethyl sulfoxide; G0/G1, growth phase 0/growth phase 1; G2/M, growth phase 2/mitosis; PI, propidium iodide.

Source: ATNXUS-KX01-001 study.

(0.13MB).
Proapoptotic Effects

In vitro treatment of the PC3-LN4 cell line with tirbanibulin induced early apoptosis, as indicated by positive annexin V staining; additional staining with 7-aminoactinomycin D reveals cells in late apoptosis or necrosis (Fig. 2).

Figure 2.

Induction of apoptosis in prostate cancer cells (PC3-LN4). A, Flow cytometry analysis of PC3-LN4 cells stained with annexin V and 7-AAD after treatment with tirbanibulin at different concentrations for 48 hours. B, Immunoblot analysis of lysed PC3-LN4 cells after 24 hours of treatment with tirbanibulin. 7-AAD indicates 7-aminoactinomycin D; GADPH, glyceraldehyde-3-phosphatase dehydrogenase; PARP, poly(ADP-ribose) polymerase.

Source: ATNXUS-KX01-001 study.

(0.27MB).

Immunoblot analysis revealed that treatment with tirbanibulin led to hyperphosphorylation of Bcl-2, cleavage of caspases 8 and 9, activation of caspase 3, and subsequent cleavage of poly (ADP-ribose) polymerase (Fig. 2B), thus demonstrating that tirbanibulin activates the intrinsic and extrinsic apoptosis signaling cascade.

These proapoptotic effects were also observed in vivo in mouse xenograft models of various tumors3,7,8.

Cell Growth Inhibition and Antiproliferative Activity

In a cell growth experiment, the effect of tirbanibulin on keratinocyte cell cultures (CCD-1106 KERTr) was studied in a complete culture medium and a growth factor–reduced medium (Fig. 3). After incubation of both keratinocyte cultures with various concentrations of tirbanibulin for 72 hours (Fig. 3B), tirbanibulin proved to be more effective for inhibition of cell growth and induction of cell death in fast-growing cells (complete medium) than in slow-growing cells (reduced medium) (Fig. 3C); the drug concentration at which 50% cell growth inhibition (IC50) was achieved was 11 nM vs. 27 nM (P < .0001, t test).

Figure 3.

Induction of cell growth inhibition and cell death in immortalized keratinocytes (CCD-1106 KERTr). A, Immortalized CCD-1106 KERTr keratinocytes were cultured in complete medium or growth factor–reduced medium (5% of complete medium) and counted at different points during incubation. B, CCD-1106 KERTr cells were treated with different concentrations of tirbanibulin and incubated in complete medium or medium with growth factor–reduced medium for 72 hours, followed by MTT analysis. C, Trypan blue staining (mean [SD] of the cell viability percentage). MTT indicates 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

Source: ATNXUS-KX01-001 study.

(0.31MB).

Studies have shown tirbanibulin to exert potent antiproliferative activity in several cancer cell lines (including cSCC, melanoma, and multidrug-resistant cancer cells). Table 1 shows the antiproliferative potency of tirbanibulin by IC50.

Table 1.

Potency of Tirbanibulin in Various Tumor Cell Lines

Source  Type of cancer  Cell line  IC50 of tirbanibulin, nM 
ATNXUS-KX01-001 study  Renal cancer  769-P  45 
    786-O  378 
    Caki-2  39 
    ACHN  33 
  Non-Hodgkin lymphoma  RL  19 
    Raji  34 
    Ramos (RA1)  15 
  Melanoma  SK-MEL-3  97 
    SK-MEL-28  51 
  Squamous cell cancer  A431  15 
  Gastric cancer  N87  15 
    SNU-1 
    KATO III  39 
    H5746T  105 
  Multidrug-resistant uterine sarcoma  MEX-SA/Dx5  34 
  Multidrug-resistant ovarian cancer  NCI/ADR-RES  56 
ATH001-01-p-00001 study  Immortalized keratinocytes  CCD-1106 KERTr  40 
Liu et al.7, 2013  Mucinous ovarian carcinoma  RMUG-S  72 
    RMUG-L  NA 
    YDOV-151  115 
    EFO-27  203 
Kim et al.3, 2017  Luminal breast cancer (ER+)  MCF7  42a 
  Luminal breast cancer (ER+/PR+)  T47D  44a 
  HER2+ breast cancer  BT-474  129a 
    SK-BR-3  34a 
  Triple-negative breast cancer  BT-549  47a 
    MDA-MB-231  45a 
    MDA-MB-468  61a 
    HCC1937  >5000a 
    Hs578T  >5000a 
Smolinski et al.6, 2018  Colon cancer  HT29  25 
  Ovarian cancer  SKOV-3  10 
  Prostate cancer  PC3-MM2 
  Pancreatic cancer  L3.6pl  25 
  Breast cancer  MDA-MB-231  20 
  Lung cancer  A549 
  Liver cancer  HuH7 
  Kidney cancer  769-P  45 
  Chronic myeloid leukemia  K562  13 
    K562R  0.64 
  Acute lymphocytic leukemia  MOLT-4  13 
    CCRF-HSB-2  12 
  T-cell leukemia  Jurkat  10 
    Ba/F3+WT BCR-Abl  85 
    Ba/F3+E225 K  80 
    Ba/F3+T3151  35 
  Acute myeloid leukemia  KG-1  16 
  Multiple myeloma  RPM18226  40 
  Non-Hodgkin lymphoma  RL  19 
Niu et al.5, 2019  Cervical cancer  HeLa  53 
  Liver cancer  HepG2  40 
  Lung cancer  H460  75 

Abbreviations: ER, estrogen receptor; IC50, inhibitory concentration 50 (drug concentration that inhibits cell proliferation by 50%); HER2, type 2 human epidermal growth factor receptor; PR, progesterone receptor.

a

Adapted from μmol/L.

The antiproliferative activity of tirbanibulin observed in vitro translates into antitumor efficacy in vivo. In breast cancer (MDA-MB-231 cells) and mucinous ovarian carcinoma (RMUG-S and RMUG-L cells) mouse xenograft models, tirbanibulin effectively delayed tumor growth and was associated with decreased expression of the proliferation marker Ki67 and with increased levels of apoptotic cells3,7.

Furthermore, in a murine human prostate cancer model (PC-3MM2GL cells), tirbanibulin showed efficacy in suppressing tumor growth at both the primary and the metastatic levels. Mean tumor weight was significantly reduced in the tirbanibulin-treated groups (5- and 10-mg/kg doses) compared to the control group (1.16 and 0.35 vs. 2.27 g, respectively). The number of lymph node metastases decreased in the groups treated with tirbanibulin (5 and 10 mg/kg) compared to the control group (4/5 and 2/5 vs. 5/5, respectively). Other studies also showed dose-dependent tumor growth inhibition with tirbanibulin in breast cancer mouse xenograft models (MCF-7 and MDA-MB-231 cells)8,9. These findings are related to microtubule disruption, G2/M deregulation, abnormal mitosis, and, ultimately, apoptosis.

Disruption of Src Signaling

Both in AK and in cSCC, increased expression of Src tyrosine kinase has been observed, and some evidence suggests that increased signaling by Src is necessary for hemidesmosome alterations, keratinocyte migration, and cSCC invasion11,12. Similarly, increased Src expression has been observed in metastatic tissues, various epithelial tumors, hyperproliferative epidermal disorders, and premalignant lesions. Furthermore, Src is involved in angiogenesis and vascular endothelial growth factor stimulation8,9,13–15. Therefore, the prevalence of increased Src in neoplasms suggests that this protein may play an important role in the progression of many tumors, showing it to be a good candidate target molecule for potential treatments16.

In addition to the effect triggered by the inhibition of tubulin polymerization, published studies have shown that exposure of various cancerous cell lines and human tumor xenografts to tirbanibulin in mice results in a rapid decrease in levels of phosphorylated Src and/or its substrates, indicating that tirbanibulin also disrupts Src signaling3,8,9.

However, Src was not identified as a direct target for tirbanibulin binding in a study designed to measure interactions between tirbanibulin and more than 450 relevant human kinases and mutant variants. Moreover, the microtubule network has been shown to regulate active Src via intracellular Src trafficking17. The data presented above suggest that tirbanibulin decreases Src activity through indirect disruption of Src signaling, probably owing to disruption of the microtubule network, which interferes with cell signaling pathways, including those that regulate Src expression and trafficking.

Necrosis, Inflammation, and Toxicity

Some drugs used in the treatment of AK (e.g., 5-fluorouracil) induce the production of proinflammatory cytokines, such as tumor necrosis factor (TNF) α and interleukin (IL) 8, which can cause local skin reactions18. A preclinical study investigated how incubation of CCD-1106 KERTr keratinocytes with tirbanibulin for 24 hours could influence the release of proinflammatory cytokines. The results showed that incubation with tirbanibulin induced only a slight increase in IL-8 at the highest dose, compared to the moderate increase in TNF-α and IL-8 elicited by 5-fluorouracil. In addition, tirbanibulin showed a significant increase in IL-1α, a marker of cell death, compared to the control (DMSO) and 5-fluorouracil19. These data suggest that tirbanibulin is less likely to induce a strong proinflammatory cytokine response than 5-fluorouracil, possibly leading to a reduction in the severity of local skin reactions.

Currently Available Topical Treatments for Actinic Keratosis

Currently, the main topical treatments available are 5-fluorouracil, diclofenac, and imiquimod. Ingenol mebutate was recently withdrawn by the European Medicines Agency18,20.

Fig. 4 summarizes the mechanism of action of each treatment and its advantages and disadvantages in the context of the molecular implications of prolonged exposure to UV light2. 5-Fluorouracil (0.5% 5-fluorouracil/10% salicylic acid) is a DNA/RNA synthesis inhibitor that induces apoptosis in rapidly dividing cells20; treatment is self-administered daily for up to 12 weeks21. Diclofenac (3%) is a nonsteroidal anti-inflammatory drug that inhibits cyclooxygenase 2, reducing angiogenesis and cell proliferation; it should be applied twice daily for 60-90 days22. Imiquimod (5% or 3.75%) is an innate immune system stimulator that induces production of interferons and various cytokines with a direct apoptotic effect on tumor cells23,24; treatment is applied by the patient 3 times a week for 4 weeks23,24. Ingenol mebutate is a biological compound extracted from the Euphorbia peplus plant whose mechanism of action is not fully characterized25. It seems to have a dual action: one is the induction of necrosis of dysplastic cells and the other is the stimulation of a neutrophil-mediated immune response20. However, following a drug safety review conducted by the European Medicines Agency, the use of ingenol mebutate for the treatment of AK is not authorized in the European Union as of 202026. One of the studies in that review showed a higher incidence of cSCC in the area treated with ingenol mebutate than in the area treated with imiquimod at a 3 year follow-up (3.3% vs. 0.4%)26.

Figure 4.

Current treatments for actinic keratosis. COX indicates cyclooxygenase; EMA, European Medicines Agency; FDA, United States Food and Drug Administration; FU, fluorouracil; IFN α: interferon alpha; LSR, local skin reaction28–30.

(0.37MB).

While effective, some of these therapies are often associated with a high frequency of severe local skin reactions (skin irritation, erosions, ulcerations, edema, crusting, itching), irreversible changes (skin pigmentation, scarring), and also with systemic adverse events at a lower frequency18,20,25. Furthermore, since prolonged therapy can reduce adherence and affect the success of treatment, there is a need to find suitable therapies with a shorter duration of use that can be applied over a wide skin area and have only mild local adverse effects on the skin27. Tirbanibulin is 1 of 6 treatments for AK currently under development in phase 2 and 3 clinical trials20.

How Does Tirbanibulin’s Novel Mechanism of Action Fit in the Treatment of Actinic Keratosis?

As shown above, tirbanibulin represents a new mechanism of action in the treatment of AK, with potent antiproliferative and antitumor effects in vitro and in vivo owing to its ability to induce cell cycle arrest and apoptotic cell death (Fig. 5). Since AK, as a precancerous skin condition, is caused by dysplastic keratinocytes with cell hyperproliferation, tirbanibulin represents a good therapeutic candidate.

Figure 5.

Mechanism of action of tirbanibulin in treatment of actinic keratitis. cSCC indicates cutaneous squamous cell carcinoma.

Source: Figure created using BioRender.com.

(0.32MB).

In phase 3 trials, 702 patients with AK on the face or scalp were randomized to treatment with tirbanibulin 1% cream (n = 353) or placebo (n = 349). Tirbanibulin met the primary endpoint after achieving complete clearance of the lesions treated at day 57 in both phase 3 trials. In the first trial, complete clearance was observed in 44% of patients in the tirbanibulin group and in only 5% of the placebo group (difference, 40 percentage points; 95% CI, 32-47; P < .001). In the second trial, the percentages were 54% and 13% for the tirbanibulin and placebo groups, respectively (difference, 42 percentage points; 95% CI, 33-51; P < .001)4.

It has to be highlighted that tirbanibulin is applied once daily for only 5 consecutive days over a 25-cm2 treatment field on the face or scalp. This simplification of the dosing regimen, in contrast to the complexity of the other available therapies for AK, facilitates patient completion of tirbanibulin treatment.

Furthermore, unlike other topical treatments and mainly owing to reduced release of cytokines, tirbanibulin does not seem to induce substantial tissue necrosis and/or inflammation, which is clinically translated into a good tolerability and a favorable safety profile.

Conclusions

Tirbanibulin is a new synthetic chemical drug that has demonstrated potent antiproliferative and antitumor activity. These effects can be attributed to the ability of tirbanibulin to bind to tubulin, inhibiting its polymerization and promoting microtubule disruption in cells, as well as indirectly altering Src tyrosine kinase signaling.

For all these reasons, and given that AK is associated with cell hyperproliferation, tirbanibulin represents a good candidate for the treatment of AK. In addition, its simple dosage regimen favors adherence to therapy. Finally, tirbanibulin does not induce a pronounced release of proinflammatory cytokines in keratinocytes in vitro, unlike other treatments for AK, such as 5-fluorouracil. This is associated with good tolerability and a favorable safety profile in clinical practice.

Funding

Athenex Inc., Buffalo, NY, USA provided financial support for our research. Almirall S.A., Barcelona provided financial support for the preparation of the article.

Conflicts of Interest

Y. Gilaberte has served as a consultant for Almirall, Isdin, Roche Posay, AbbVie, Lilly, Sanofi, and Pfizer. Dr. Gilaberte has also received research grants from Galderma, Vichy, Sanofi, and Almirall and as a speaker for Galderma, Roche Posay, Isdin, Avene, Cantabria Labs, and Rilastil.

M.T. Fernández-Figueras has received grants from Leo Pharma and Almirall and has participated as a speaker for Almirall, Galderma, Leo Pharma, Novartis, and Roche.

Acknowledgments

The authors would like to thank Irene Mansilla, MSc, Eva Mateu, PhD, and Paula Casajust, MSc from TFS S.L. for their support during the preparation of the manuscript.

References
[1]
M.T. Fernandez Figueras.
From actinic keratosis to squamous cell carcinoma: pathophysiology revisited.
J Eur Acad Dermatol Venereol., 31 (2017), pp. 5-7
[2]
B. Berman, C.J. Cockerell.
Pathobiology of actinic keratosis: ultraviolet-dependent keratinocyte proliferation.
J Am Acad Dermatol., 68 (2013), pp. S10-19
[3]
S. Kim, A. Min, K.-H. Lee, Y. Yang, T.-Y. Kim, J.M. Lim, et al.
Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis.
Cancer Res Treat Off J Korean Cancer Assoc., 49 (2017), pp. 643-655
[4]
A. Blauvelt, S. Kempers, E. Lain, T. Schlesinger, S. Tyring, S. Forman, et al.
Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis.
N Engl J Med., 384 (2021), pp. 512-520
[5]
L. Niu, J. Yang, W. Yan, Y. Yu, Y. Zheng, H. Ye, et al.
Reversible binding of the anticancer drug KXO1 (tirbanibulin) to the colchicine-binding site of β-tubulin explains KXO1’s low clinical toxicity.
J Biol Chem., 294 (2019), pp. 18099-18108
[6]
M.P. Smolinski, Y. Bu, J. Clements, I.H. Gelman, T. Hegab, D.L. Cutler, et al.
Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361).
J Med Chem., 61 (2018), pp. 4704-4719
[7]
T. Liu, W. Hu, H.J. Dalton, H.J. Choi, J. Huang, Y. Kang, et al.
Targeting Src and tubulin in mucinous ovarian carcinoma.
Clin Cancer Res Off J Am Assoc Cancer Res., 19 (2013),
[8]
M. Anbalagan, A. Ali, R.K. Jones, C.G. Marsden, M. Sheng, L. Carrier, et al.
Peptidomimetic Src/pretubulin inhibitor KX-01 alone and in combination with paclitaxel suppresses growth, metastasis in human ER/PR/HER2-negative tumor xenografts.
Mol Cancer Ther., 11 (2012), pp. 1936-1947
[9]
M. Anbalagan, L. Carrier, S. Glodowski, D. Hangauer, B. Shan, B.G. Rowan.
KX-01, a novel Src kinase inhibitor directed toward the peptide substrate site, synergizes with tamoxifen in estrogen receptor α positive breast cancer.
Breast Cancer Res Treat., 132 (2012), pp. 391-409
[10]
S. Zitouni, C. Nabais, S.C. Jana, A. Guerrero, M. Bettencourt-Dias.
Polo-like kinases: structural variations lead to multiple functions.
Nat Rev Mol Cell Biol., 15 (2014), pp. 433-452
[11]
S.A. Ainger, R.A. Sturm.
Src and SCC: getting to the FAKs.
Exp Dermatol., 24 (2015), pp. 487-488
[12]
A. Mariotti, P.A. Kedeshian, M. Dans, A.M. Curatola, L. Gagnoux-Palacios, F.G. Giancotti.
EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion.
J Cell Biol., 155 (2001), pp. 447-458
[13]
J.M. Summy, G.E. Gallick.
Src family kinases in tumor progression and metastasis.
Cancer Metastasis Rev., 22 (2003), pp. 337-358
[14]
N. Munshi, J.E. Groopman, P.S. Gill, R.K. Ganju.
c-Src mediates mitogenic signals and associates with cytoskeletal proteins upon vascular endothelial growth factor stimulation in Kaposi’s sarcoma cells.
J Immunol Baltim Md., 164 (2000), pp. 1169-1174
[15]
S.I. Park, A.N. Shah, J. Zhang, G.E. Gallick.
Regulation of angiogenesis and vascular permeability by Src family kinases: opportunities for therapeutic treatment of solid tumors.
Expert Opin Ther Targets., 11 (2007), pp. 1207-1217
[16]
J.M. Summy, G.E. Gallick.
Treatment for advanced tumors: SRC reclaims center stage.
Clin Cancer Res Off J Am Assoc Cancer Res., 12 (2006), pp. 1398-1401
[17]
B. Wu, B. Decourt, M.A. Zabidi, L.T. Wuethrich, W.H. Kim, Z. Zhou, et al.
Microtubule-mediated Src tyrosine kinase trafficking in neuronal growth cones.
Mol Biol Cell., 19 (2008), pp. 4611-4627
[18]
D. de Berker, J.M. McGregor, M.F. Mohd Mustapa, L.S. Exton, B.R. Hughes.
British Association of Dermatologists’ guidelines for the care of patients with actinic keratosis 2017.
Br J Dermatol., 176 (2017), pp. 20-43
[19]
L. Pitzonka, M. Cutler, Y. Bu, A. Blanco, E. Fumero, A. Torra, et al.
465 Tirbanibulin, a novel anti-proliferative and pro-apoptotic agent for the treatment of actinic keratosis.
J Invest Dermatol., 141 (2021), pp. S81
[20]
P. Cramer, E. Stockfleth.
Actinic keratosis: where do we stand and where is the future going to take us?.
Expert Opin Emerg Drugs., 25 (2020), pp. 49-58
[21]
Efudex - FDA prescribing information, side effects and uses. Drugs.com [Accessed 27 Dec 2020]. Available from: https://www.drugs.com/pro/efudex.html.
[22]
Solaraze 3% Gel - Summary of Product Characteristics (SmPC) - (emc) [Accessed 27 Dec 2020]. Available from: https://www.medicines.org.uk/emc/product/6385/smpc.
[23]
Aldara 5% Cream - Summary of Product Characteristics (SmPC) - (emc) [Accessed 8 Jan 2021]. Available from: https://www.medicines.org.uk/emc/medicine/8#PHARMACOLOGICAL_PROPS.
[24]
Zyclara 3.75% cream - Summary of Product Characteristics (SmPC) - (emc) [Accessed 20 Apr 2021]. Available from: https://www.medicines.org.uk/emc/medicine/27323#gref.
[25]
B. Dréno, J.M. Amici, N. Basset-Seguin, B. Cribier, J.P. Claudel, M.A. Richard, et al.
Management of actinic keratosis: a practical report and treatment algorithm from AKTeam™ expert clinicians.
J Eur Acad Dermatol Venereol., 28 (2014), pp. 1141-1149
[26]
European Medicines Agency. Risks of Picato for actinic keratosis outweigh benefits. 2020 [Accessed 1 Oct 2020]. Available from: https://www.ema.europa.eu/en/documents/referral/picato-article-20-referral-risks-picato-actinic-keratosis-outweigh-benefits_en.pdf.
[27]
G. Goldenberg.
Treatment considerations in actinic keratosis.
J Eur Acad Dermatol Venereol., 31 (2017), pp. 12-16
[28]
A.K. Gupta, M. Paquet.
Network meta-analysis of the outcome “participant complete clearance” in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review.
Br J Dermatol., 169 (2013), pp. 250-259
[29]
Picato 150 mcg/g Gel - Summary of Product Characteristics (SmPC) - (emc) [Accessed 8 Jan 2021]. Available from: https://www.medicines.org.uk/emc/product/2888/smpc.
[30]
Picato 500 mcg/g Gel - Summary of Product Characteristics (SmPC) - (emc) [Accessed 8 Jan 2021]. Available from: https://www.medicines.org.uk/emc/product/2889/smpc.

Please cite this article as: Gilaberte Y, Fernández-Figueras MT. Tirbanibulina: revisión de su mecanismo de acción novedoso y de cómo encaja en el tratamiento de la queratosis actínica. Actas Dermosifiliogr. 2021. https://doi.org/10.1016/j.ad.2021.07.006

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