P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: Implication in cancer therapy

Fernández-Aroca, Diego M.; Roche, Olga; Sabater, S.; Pascual-Serra, Raquel; Ortega-Muelas, Marta; Sanchez-Perez, Isabel; Belandia, Borja; Ruiz-Hidalgo, Marı́a José; Sánchez‐Prieto, Ricardo

doi:10.1016/j.canlet.2019.02.049

Cited by 46 publications

(50 citation statements)

References 52 publications

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“…Cancer radiosensitizers are promising agents that enhance injury to tumor tissue by accelerating DNA damage and producing free radicals [13]. Several strategies to improve the therapeutic ratio are currently under investigation to enhance the radiation effect, thereby preventing tumor recurrence or progression [13,14,15,16]. In melanoma, there is a compelling rationale to identify promising molecular targeting agents that may sensitize melanoma to radiation.…”

Section: Introductionmentioning

confidence: 99%

The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma

Krayem

Sabbah

Najem

et al. 2019

Cancers

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Radiotherapy (RT) in patients with melanoma historically showed suboptimal results, because the disease is often radioresistant due to various mechanisms such as scavenging free radicals by thiols, pigmentary machinery, or enhanced DNA repair. However, radiotherapy has been utilized as adjuvant therapy after the complete excision of primary melanoma and lymph nodes to reduce the rate of nodal recurrences in high-risk patients. The resistance of melanoma cells to radiotherapy may also be in relation with the constitutive activation of the MAPK pathway and/or with the inactivation of p53 observed in about 90% of melanomas. In this study, we aimed to assess the potential benefit of adding RT to BRAF-mutated melanoma cells under a combined p53 reactivation and MAPK inhibition in vitro and in a preclinical animal model. We found that the combination of BRAF inhibition (vemurafenib, which completely shuts down the MAPK pathway), together with p53 reactivation (PRIMA-1Met) significantly enhanced the radiosensitivity of BRAF-mutant melanoma cells. This was accompanied by an increase in both p53 expression and activity. Of note, we found that radiation alone markedly promoted both ERK and AKT phosphorylation, thus contributing to radioresistance. The combination of vemurafenib and PRIMA-1Met caused the inactivation of both MAPK kinase and PI3K/AKT pathways. Furthermore, when combined with radiotherapy, it was able to significantly enhance melanoma cell radiosensitivity. Interestingly, in nude mice bearing melanoma xenografts, the latter triple combination had not only a synergistic effect on tumor growth inhibition, but also a potent control on tumor regrowth in all animals after finishing the triple combination therapy. RT alone had only a weak effect. In conclusion, we provide a basis for a strategy that may overcome the radioresistance of BRAF-mutated melanoma cells to radiotherapy. Whether this will translate into a rational to use radiotherapy in the curative setting in BRAF-mutated melanoma patients deserves consideration.

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Section: Introductionmentioning

confidence: 99%

The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma

Krayem

Sabbah

Najem

et al. 2019

Cancers

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“…A possible explanation was that p53 is a key effector in IR-induced cellular response and the lack of p53 was associated with increased radioresistance [59]. This hypothesis was confirmed by Fernández-Aroca et al [49], who reported that p53 was a critical determinant of palbociclib-associated radiosensitivity. Dean et al [37] shared similar findings in breast cancer given that the response of Rad51 to palbociclib with IR presented in an RB-dependent manner.…”

Section: Mechanisms Of Cdk4/6 Inhibitors As Radiosensitizersmentioning

confidence: 81%

“…The γ-H2AX level rapidly increased in H460 (7.9-fold) and H1299 (6.7-fold) cells 0.5 h after IR compared to untreated control. Additional studies also demonstrated that various post-irradiated cell lines showed substantial increases in γ-H2AX and (or) 53BP1 foci, which eventually led to increased DSBs [ 37 , 42 , 45 – 47 , 49 ].…”

Section: Mechanisms Of Cdk4/6 Inhibitors As Radiosensitizersmentioning

confidence: 99%

CDK4/6 inhibitors: a novel strategy for tumor radiosensitization

Yang

Luo

Chen

et al. 2020

J Exp Clin Cancer Res

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Recently, the focus of enhancing tumor radiosensitivity has shifted from chemotherapeutics to targeted therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a novel class of selective cell cycle therapeutics that target the cyclin D-CDK4/6 complex and induce G1 phase arrest. These agents have demonstrated favorable effects when used as monotherapy or combined with endocrine therapy and targeted inhibitors, stimulating further explorations of other combination strategies. Multiple preclinical studies have indicated that CDK4/6 inhibitors exhibit a synergistic effect with radiotherapy both in vitro and in vivo. The principal mechanisms of radiosensitization effects include inhibition of DNA damage repair, enhancement of apoptosis, and blockade of cell cycle progression, which provide the rationale for clinical use. CDK4/6 inhibitors also induce cellular senescence and promote anti-tumor immunity, which might represent potential mechanisms for radiosensitization. Several small sample clinical studies have preliminarily indicated that the combination of CDK4/6 inhibitors and radiotherapy exhibited well-tolerated toxicity and promising efficacy. However, most clinical trials in combined therapy remain in the recruitment stage. Further work is required to seek optimal radiotherapy-drug combinations. In this review, we describe the effects and underlying mechanisms of CDK4/6 inhibitors as a radiosensitizer and discuss previous clinical studies to evaluate the prospects and challenges of this combination.

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“…The concurrent administration of a drug with radio-sensitizing activity could therefore be a valuable mean to improve symptomatic and disease control. CDK4/6 inhibitors demonstrated radio-sensitizing effects not only on breast cancer 25 , but also on several other tumor cell lines, including colorectal carcinoma 25 , lung cancer 25,26 , atypical teratoid rhabdoid tumor 27 , glioblastoma 27,28 , hepatocellular carcinoma 29 , cholangiocarcinoma 29 and head and neck squamous carcinoma 30 . Despite these promising activity, the lack of a substantial body of clinical literature might persuade clinicians to avoid the concomitant administration of RT and CDK4/6 inhibitors, as radio-sensitizing effect could potentially involve also healthy tissues and lead to increased toxicity.…”

Section: Resultsmentioning

confidence: 99%

A single-center retrospective safety analysis of cyclin-dependent kinase 4/6 inhibitors concurrent with radiation therapy in metastatic breast cancer patients

Guerini

Pedretti

Salah

et al. 2020

Sci Rep

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Cyclin dependent kinases 4/6 (CDK4/6) inhibitors gained an essential role in the treatment of metastatic breast cancer. Nevertheless, data regarding their use in combination with radiotherapy are still scarce. We performed a retrospective preliminary analysis of breast cancer patients treated at our Center with palliative radiation therapy and concurrent CDK4/6 inhibitors. Toxicities were measured according to CTCAE 4.0, local response according to RECIST 1.1 or PERCIST 1.0 and pain control using verbal numeric scale. 18 patients (32 treated sites) were identified; 50% received palbociclib, 33.3% ribociclib and 16.7% abemacliclib. Acute non-hematologic toxicity was fair, with the only exception of a patient who developed G3 ileitis. During 3 months following RT, 61.1% of patients developed G 3-4 neutropenia; nevertheless no patient required permanent suspension of treatment. Pain control was complete in 88.2% of patients three months after radiotherapy; 94.4% of patients achieved and maintained local control of disease. Radiotherapy concomitant to CDK4/6 inhibitors is feasible and characterized by a fair toxicity profile, with isolated episodes of high-grade reversible intestinal toxicity. Rate of G 3-4 neutropenia was comparable with that measured for CDK4/6 inhibitors alone. Promising results were reported in terms of pain relief and local control of disease. Selective cyclin dependent kinases 4/6 (CDK4/6) inhibitors block tumor suppressor retinoblastoma protein phosphorylation, preventing the transition of cancer cells from G1 to S phase with consequent inhibition of cell cycle and proliferation 1. To date, three CDK4/6 inhibitors are approved against hormone receptor positive, human epidermal growth factor receptor 2 negative metastatic or advanced breast cancer in combination with aromatase inhibitors or fulvestrant both in first and subsequent lines of therapy. After different phase III trials 2-7 reporting significant improvements in response rate and progression free survival, palbociclib was the

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P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: Implication in cancer therapy

Cited by 46 publications

References 52 publications

The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma

The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma

CDK4/6 inhibitors: a novel strategy for tumor radiosensitization

A single-center retrospective safety analysis of cyclin-dependent kinase 4/6 inhibitors concurrent with radiation therapy in metastatic breast cancer patients

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