Drug-induced pneumonitis in cancer patients treated with mTOR inhibitors: management and insights into possible mechanisms

Durán, Ignacio; Goebell, Peter-Jürgen; Papazisis, Konstantinos; Ravaud, Alain; Weichhart, Thomas; Rodríguez-Portal, José Antonio; Budde, Klemens

doi:10.1517/14740338.2014.888056

Cited by 31 publications

(37 citation statements)

References 54 publications

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“…Transplant and cancer patients are currently treated with either rapamycin or everolimus. Noninfectious DIP is experienced with both inhibitors and occurs in about 3-30% of patients depending on the study analysis but probably independent from trough levels [14][15][16][17].…”

Section: Discussionmentioning

confidence: 99%

“…The molecular causes of noninfectious mTOR-inhibitor induced pneumonitis are currently unclear, however important to understand to better manage or interfere with this side effect [17]. The elucidation of the molecular mechanisms might allow better management options for DIP and may also pave the way to uncouple the desired effects of mTOR inhibitors from their unwanted side effects.…”

Section: Discussionmentioning

confidence: 99%

“…Transplant patients and renal cell carcinoma patients treated with the mTOR inhibitors rapamycin or everolimus experience noninfectious drug-induced pneumonitis (DIP) [14][15][16][17]. Moreover, breast cancer patients treated with everolimus similarly develop DIP [18] suggesting that DIP is common to all mTOR inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Effects of the mTOR inhibitor everolimus and the PI3K/mTOR inhibitor NVP-BEZ235 in murine acute lung injury models

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et al. 2015

Transplant Immunology

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The mammalian target of rapamycin (mTOR) is a key signaling kinase associated with a variety of cellular functions including the regulation of immunological and inflammatory responses. Classic mTOR inhibitors such as rapamycin or everolimus are commonly used in transplant as well as cancer patients to prevent transplant rejection or cancer progression, respectively. Noninfectious drug-induced pneumonitis is a frequent side effect in mTOR-inhibitor-treated patients. Therefore, we tested the effects of the mTOR inhibitor everolimus and the novel dual PI3K/mTOR inhibitor NVP-BEZ235 in a murine lipopolysaccharide (LPS)-induced acute lung injury model. C57BL/6 mice were treated with either everolimus or NVP-BEZ235 on two consecutive days prior to intratracheal administration of LPS. LPS administration induced a significant increase in total cell, neutrophil and erythrocyte numbers in the bronchoalveolar lavage fluid. Histological examination revealed a serious lung injury as shown by interstitial edema, vascular congestion and mononuclear cell infiltration in these mice after 24h. Everolimus as well as NVP-BEZ235 did not noticeably affect overall histopathology of the lungs in the lung injury model. However, NVP-BEZ235 enhanced IL-6 and TNF-α expression after 24h. In contrast, everolimus did not affect IL-6 and TNF-α levels. Interestingly, both inhibitors reduced inflammatory cytokines in an LPS/oleic acid-induced lung injury model. In conclusion, the mTOR inhibitors did not worsen the overall histopathological severity, but they exerted distinct effects on proinflammatory cytokine expression in the lung depending on the lung injury model applied.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of the mTOR inhibitor everolimus and the PI3K/mTOR inhibitor NVP-BEZ235 in murine acute lung injury models

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Preitschopf

et al. 2015

Transplant Immunology

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“…Interestingly, patients with a variety of diseases, including those with breast cancer and renal cell carcinoma as well as transplant recipients, treated with the rapamycin or the rapamycin derivative everolimus have an increased tendency to develop noninfectious drug-induced pneumonitis (29). These symptoms, which occur in up to one-third of treated patients depending upon the clinical study, are usually mild, and only around 10% of patients require treatment.…”

Section: Mtor In Disease and Agingmentioning

confidence: 99%

Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging

Kennedy

Pennypacker

2016

Annals ATS

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“…However, druginduced pneumonitis has also been observed with mTOR inhibitors, where immune-and host-mediated factors have been implicated, possibly through pro-inflammatory activation of the innate immune system, mediated by effects on monocytes or macrophages. 96 Thus, pneumonitis may be a toxicity resulting from the inhibition of PI3K/AKT/mTOR signaling.…”

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The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

Wiestner

2015

Haematologica

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Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic leukemia with B-cell receptor inhibitors, and summarizes the clinical experience with these agents. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia Adrian WiestnerHematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA ABSTRACT junction genes (J) in order to form a novel, unique sequence that encodes the antigen binding domain of the BCR (Figure 1). In theory, billions of different combinations are possible, generating a vastly diverse repertoire of possible antigen binding sites. However, CLL cells display a highly restricted, non-random repertoire of different immunoglobulin heavy chain variable (IGHV) region genes, suggesting that CLL cells have distinct antigen specificities. 15,18,19 Furthermore, the presence or absence of somatic mutations in the clonal IGHV gene, a mark of antigenic selection, distinguishes two major CLL subtypes; IGHV mutated (M-CLL) and IGHV unmutated (U-CLL); the latter having more than 98% sequence homology of the clonal IGHV g...

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Drug-induced pneumonitis in cancer patients treated with mTOR inhibitors: management and insights into possible mechanisms

Cited by 31 publications

References 54 publications

Effects of the mTOR inhibitor everolimus and the PI3K/mTOR inhibitor NVP-BEZ235 in murine acute lung injury models

Effects of the mTOR inhibitor everolimus and the PI3K/mTOR inhibitor NVP-BEZ235 in murine acute lung injury models

Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging

The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia

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