Phosphoinositid-3-Kinase-Inhibitors, cutaneous side effects

PI 3-kinases(phosphoinositide 3-kinases, PI 3-Ks) are a family of lipid kinases that are able to phosphorylate 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 one of the most frequently activated signaling pathways in human cancer.

There are currently five approved PI3K inhibitors:

• idelalisib
• Alpelisib (also approved for PIK3CA-associated overgrowth syndromes)
• Copanlisib
• duvelisib
• umbralisib.

Others are currently 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 exanthematic skin reactions. Based on a cumulative sample size of 4,200 participants from 15 studies, the incidence of cutaneous events of any grade with PI3K inhibitors was found to be 29.30% (Wang Y et al. 2022).

The underlying pathogenesis of PI3K inhibitor eruptions is not fully understood. The PI3K/Akt/mTOR signaling pathway plays an important role in the differentiation of keratinocytes. Inhibition of this process leads to modulation of growth factors resulting in epidermal cell death. When oncolytic agents target molecular pathways of cell proliferation (this is the case with PI3K inhibitors), a wide range of dermatological side effects can be expected. In the case of PI3K inhibitors, these range from a mild maculopapular rash to life-threatening toxic epidermal necrolysis. Exfoliative and multiforme exanthema of varying severity have been described. Furthermore, a "drug reaction with eosinophilia and systemic symptoms" DRESS was observed 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.