Trametinib radiosensitises RAS- and BRAF-mutated melanoma by perturbing cell cycle and inducing senescence

Schick, Ulrike; Kyula, Joan; Barker, Holly E.; Patel, Radhika R.; Zaidi, Shane; Gregory, C. Ippolito; Hafsi, Hind; Roulstone, Victoria; Deutsch, Éric; McLaughlin, Martin; Harrington, Kevin

doi:10.1016/j.radonc.2015.06.026

Cited by 41 publications

(29 citation statements)

References 21 publications

(28 reference statements)

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“…Reducing HRAS is sufficient to drive a quiescent cell into senescence as marked by the accumulation of SA-β-gal, HP1γ SAHF and stable growth arrest, and enforced expression of HRAS could prevent progression of cells into a stable senescent state and prevent the increase in ATRX foci formation. This is consistent with other findings that reported that repression of RAS signaling is required to establish the senescent state in cell lines and mouse models 58 – 62 . Consequently, the loss of ATRX during the development of tumors and its repression of HRAS expression may contribute to overcoming senescence, similar to how more well known mutations in the feedback loops affect signaling flux through the RAS pathway 63 , 64 .…”

Section: Discussionsupporting

confidence: 93%

ATRX is a regulator of therapy induced senescence in human cells

et al. 2017

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Senescence is a state of stable cell cycle exit with important implications for development and disease. Here, we demonstrate that the chromatin remodeling enzyme ATRX is required for therapy-induced senescence. ATRX accumulates in nuclear foci and is required for therapy-induced senescence in multiple types of transformed cells exposed to either DNA damaging agents or CDK4 inhibitors. Mobilization into foci depends on the ability of ATRX to interact with H3K9me3 histone and HP1. Foci form soon after cells exit the cell cycle, before other hallmarks of senescence appear. Eliminating ATRX in senescent cells destabilizes the senescence-associated heterochromatic foci. Additionally, ATRX binds to and suppresses expression from the HRAS locus; repression of HRAS is sufficient to promote the transition of quiescent cells into senescence and preventing repression blocks progression into senescence. Thus ATRX is a critical regulator of therapy-induced senescence and acts in multiple ways to drive cells into this state.

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Section: Discussionsupporting

confidence: 93%

ATRX is a regulator of therapy induced senescence in human cells

et al. 2017

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“…It is unclear whether BRAFi should be held before, during, and after RT and, if so, how long. Even less is known about MEKi and RT interactions, although recent data suggest in vitro and in vivo radiosensitization from the combination (14, 15). …”

Section: Introductionmentioning

confidence: 99%

Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG)

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Grossmann

Atkins

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

140

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BRAF kinase gene V600 point mutations drive approximately 40% to 50% of all melanomas, and BRAF inhibitors (BRAFi) have been found to significantly improve survival outcomes. Although radiation therapy (RT) provides effective symptom palliation, there is a lack of toxicity and efficacy data when RT is combined with BRAFi, including vemurafenib and dabrafenib. This literature review provides a detailed analysis of potential increased dermatologic, pulmonary, neurologic, hepatic, esophageal, and bowel toxicity from the combination of BRAFi and RT for melanoma patients described in 27 publications. Despite 7 publications noting potential intracranial neurotoxicity, the rates of radionecrosis and hemorrhage from whole brain RT (WBRT), stereotactic radiosurgery (SRS), or both do not appear increased with concurrent or sequential administration of BRAFis. Almost all grade 3 dermatitis reactions occurred when RT and BRAFi were administered concurrently. Painful, disfiguring nondermatitis cutaneous reactions have been described from concurrent or sequential RT and BRAFi administration, which improved with topical steroids and time. Visceral toxicity has been reported with RT and BRAFi, with deaths possibly related to bowel perforation and liver hemorrhage. Increased severity of radiation pneumonitis with BRAFi is rare, but more concerning was a potentially related fatal pulmonary hemorrhage. Conversely, encouraging reports have described patients with leptomeningeal spread and unresectable lymphadenopathy rendered disease free from combined RT and BRAFi. Based on our review, the authors recommend holding BRAFi and/or MEK inhibitors ≥3 days before and after fractionated RT and ≥1 day before and after SRS. No fatal reactions have been described with a dose <4 Gy per fraction, and time off systemic treatment should be minimized. Future prospective data will serve to refine these recommendations.

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“…Preclinical studies with human or dog melanoma cell line xenografts in immunocompromised mice demonstrated synergy between trametinib or binimetinib and the ERBB inhibitor afatinib [17], metformin [36], vincristine [26], the ROCK inhibitor fasudil [35], the PKC inhibitor AEB071 [8], the PI3K inhibitor BEZ235 [37], and radiotherapy [31]. However, none of these combinations have been tested clinically.…”

Section: Discussionmentioning

confidence: 99%

Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients

et al. 2017

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This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy.Key pointsDigoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.

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Trametinib radiosensitises RAS- and BRAF-mutated melanoma by perturbing cell cycle and inducing senescence

Cited by 41 publications

References 21 publications

ATRX is a regulator of therapy induced senescence in human cells

ATRX is a regulator of therapy induced senescence in human cells

Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG)

Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients

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