Phosphoinositid-3-Kinase-Inhibitors, cutaneous side effects

PI 3-kinases(phosphoinositide 3-kinases, PI 3-Ks) are a family of lipid kinases capable of phosphorylating the 3'OH of the inositol ring of phosphoinositides. Thus, the phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in the regulation of various cellular processes, including proliferation, adhesion, survival, and motility. It is among the most frequently activated signaling pathways in human cancers.

Currently, there are five approved PI3K inhibitors:

• Idelalisib
• Alpelisib
• Copanlisib
• Duvelisib
• Umbralisib.

Others are in development.

The use of currently approved PI3K inhibitors as adjuvant treatment in various oncology indications is associated with several serious side effects. Many of these are immune-mediated, such as pneumonitis, hepatotoxic effects, severe diarrhea with or without colitis, and exanthematous skin reactions. Based on a cumulative sample size of 4,200 participants from 15 trials, the incidence of cutaneous events of any grade among PI3K inhibitors was found to be 29.30% (Wang Y et al. 2022) .

The underlying pathogenesis of PI3K inhibitor disruptions is not fully understood. The PI3K/Akt/mTOR pathway plays an important role in keratinocyte differentiation. Inhibition of this process results in modulation of growth factors leading to epidermal cell death. When oncololgics target molecular pathways of cell proliferation (this is the case with PI3K inhibitors), a wide range of dermatologic side effects can be expected. For PI3K inhibitors, these range from a mild maculopapular rash to life-threatening toxic epidermal necrolysis. Thus, exfoliative and multiforme exanthems of varying severity have been described. Furthermore, a "drug reaction with eosinophilia and systemic symptoms" DRESS was reported after application of alpelisib (Majeed U et al. 2021).

The following spectrum of side effects is available for idelalisib:

• Diarrhea: 56%
• fatigue: 56%
• Dizziness: 39
• Exanthema: 39
• Neutropenia: 69
• Anemia: 48%
• Thrombocytopenia: 39%

• Coutré SE et al. (2015) Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 56:2779-2786.
• Flinn IW et al (2014) Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood123:3406-3413.
• Huilaja L et al (2018) A slowly developed severe cutaneous adverse reaction to idelalisib. J Eur Acad Dermatol Venereol. 32:e192-e193.
• Jfri A et al. (2022) Incidence of Cutaneous Adverse Events With Phosphoinositide 3-Kinase Inhibitors as Adjuvant Therapy in Patients With Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 8:1635-1643.
• Majeed U et al. (2021) Case Report: Alpelisib-Induced Drug Reaction With Eosinophilia and Systemic Symptoms: A Rare Manifestation of a Common Side Effect. Front. Oncol
• Shan W et al (2022) Adverse events in lymphoma patients treated with phosphoinositide 3 kinase inhibitor in clinical trials: a meta-analysis. Ann Hematol 101:1741-1753.
• Wang Y et al. (2022) Risk of cutaneous adverse events in cancer patients treated with phosphatidylinositol 3-kinase inhibitors: A systematic review and meta-analysis of randomized controlled trials. Cancer Med doi: 10.1002/cam4.5153.