Idelalisib may have the potential to increase radiotherapy side effects

Gryc, Thomas; Putz, Florian; Goerig, Nicole L.; Ziegler, Sonia; Fietkau, Rainer; Distel, Luitpold; Schuster, Barbara

doi:10.1186/s13014-017-0827-7

Cited by 5 publications

(7 citation statements)

References 16 publications

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“…A combination with modern KI targeting the DNA damage repair network could increase the effectiveness of IR and improve tumor control, which is a highly desirable goal given the currently still poor outcome of HNSCC patients [ 3 , 13 , 16 , 17 ]. However, combination therapy also bears the risk of increased unwanted side effects on the surrounding normal tissue [ 29 ]. KI from the DNA-DDR pathways have become more and more common in oncology [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Faulhaber

Jost

Symank

et al. 2021

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(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.

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Section: Discussionmentioning

confidence: 99%

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Faulhaber

Jost

Symank

et al. 2021

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“…Radiosensitivity was analyzed using three-color FISH and measured in B/M. Cohorts “healthy”, “tumor” and “sensitive patients” were historical control cohorts as published previously [ 18 ]. The inhibitor cohorts were collected from patients of the radiation oncology department of the University Hospital Erlangen.…”

Section: Resultsmentioning

confidence: 99%

“…This is known for BRAF inhibitors such as vemurafenib. Increased side effects and cytotoxicity were noticed and therefore pausing the KI treatment is recommended for this group of targeted therapies [ 8 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…A historical cohort of cancer patients served as the control cohort. Patients with remarkable radiation-related chronic toxicity of ≥ grade 3 according to the Radiation Therapy Oncology Group (RTOG), e.g., fibrosis (grade 3 or 4) and bladder contracture after irradiation, were defined as “sensitive” to ionizing radiation (IR) and used as positive control [ 6 , 18 , 19 ]. In the current study, blood samples of patients with systemic therapy with kinase inhibitors were collected to study their individual radiosensitivity.…”

Section: Methodsmentioning

confidence: 99%

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Kinase inhibitors increase individual radiation sensitivity in normal cells of cancer patients

et al. 2022

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Purpose Kinase inhibitors (KI) are known to increase radiosensitivity, which can lead to increased risk of side effects. Data about interactions of commonly used KI with ionizing radiation on healthy tissue are rare. Patients and methods Freshly drawn blood samples were analyzed using three-color FISH (fluorescence in situ hybridization) to measure individual radiosensitivity via chromosomal aberrations after irradiation (2 Gy). Thresholds of 0.5 and 0.6 breaks/metaphase (B/M) indicate moderate or clearly increased radiosensitivity. Results The cohorts consisted of healthy individuals (NEG, n = 219), radiosensitive patients (POS, n = 24), cancer patients (n = 452) and cancer patients during KI therapy (n = 49). In healthy individuals radiosensitivity (≥ 0.6 B/M) was clearly increased in 5% of all cases, while in the radiosensitive cohort 79% were elevated. KI therapy increased the rate of sensitive patients (≥ 0.6 B/M) to 35% significantly compared to 19% in cancer patients without KI (p = 0.014). Increased radiosensitivity of peripheral blood mononuclear cells (PBMCs) among patients occurred in six of seven KI subgroups. The mean B/M values significantly increased during KI therapy (0.47 ± 0.20 B/M without compared to 0.50 ± 0.19 B/M with KI, p = 0.047). Conclusions Kinase inhibitors can intensify individual radiosensitivity of PBMCs distinctly in 85% of tested drugs.

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“…Noticeably, some DNA damage repair protein inhibitors targeting double-strand break repair proteins are also known to influence radiation therapy on a cellular level [14]. However, an increased risk of side effects after simultaneous therapy with kinase inhibitors and irradiation is described [15,16]. Based on commonly used melanoma cell lines Weigert/Jost et al [17] have done a first overview study about the influence of the two PARPi Niraparib and Talazoparib in combination with ionizing radiation on melanoma cell cultures in vitro.…”

Section: Introductionmentioning

confidence: 99%

PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation

Jonuscheit

Jost

Gajdošová

et al. 2021

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(1) Background: Niraparib and Talazoparib are poly (ADP-ribose) polymerase (PARP) 1/2 inhibitors. It is assumed that combining PARP inhibitors with radiotherapy could be beneficial for cancer treatment. In this study, melanoma cells were treated with Niraparib and Talazoparib in combination with ionizing radiation (IR). (2) Methods: The effects of Talazoparib and Niraparib in combination with IR on cell death, clonogenicity and cell cycle arrest were studied in healthy primary fibroblasts and primary melanoma cells. (3) Results: The melanoma cells had a higher PARP1 and PARP2 content than the healthy fibroblasts, and further increased their PARP2 content after the combination therapy. PARP inhibitors both sensitized fibroblasts and melanoma cells to IR. A clear supra-additive effect of KI+IR treatment was detected in two melanoma cell lines analyzing the surviving fraction. The cell death rate increased in the healthy fibroblasts, but to a larger extent in melanoma cells after combined treatment. Finally, a lower percentage of cells in the radiosensitive G2/M phase is present in the healthy fibroblasts compared to the melanoma cells. (4) Conclusions: Both PARP inhibitors sensitize melanoma cells to IR. Healthy tissue seems to be less affected than melanoma cells. However, the great heterogeneity of the results suggests prior testing of the tumor cells in order to personalize the treatment.

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Idelalisib may have the potential to increase radiotherapy side effects

Cited by 5 publications

References 16 publications

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Kinase inhibitors increase individual radiation sensitivity in normal cells of cancer patients

PARP Inhibitors Talazoparib and Niraparib Sensitize Melanoma Cells to Ionizing Radiation

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