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Table 3 Examples of sporadic and hereditary conditions and of somatic mosaic non-malignant conditions that have been treated successfully in animal models or in patients by targeting underlying “oncogenic” drivers using drugs, some of which were developed for cancer

From: The paradox of cancer genes in non-malignant conditions: implications for precision medicine

Condition Underlying molecular defect Therapy Result of therapy Comments FDA-approved drug: cancers treated
Sporadic conditions
 Rheumatoid arthritis TP53 mutations Tocilizumab, which is an anti-IL-6 receptor antibody Decreased incidence of flares, better disease control [169] Efficacy in humans; TP53 mutations are known to increase IL-6, which mediates inflammation [142] None
 Desmoid tumors CTNNB1 mutations COX-2 inhibitors and sorafenib Tumor regression [5, 145, 146] Efficacy in humans; COX-2 inhibitors and sorafenib can abrogate the activation of the WNT pathway by CTNNB1 alterations [13, 41, 42] COX-2 inhibitors: none
Sorafenib: renal cell carcinoma, hepatocellular carcinoma
 Inflammatory myofibroblastic tumors ALK rearrangements Crizotinib Sustained objective responses [30] Efficacy in humans; crizotinib is a potent ALK inhibitor Non-small cell lung cancer
 Schnitzler syndrome MYD88 L265P mutation Anakinra, which is an IL-1 antagonist Complete remission of disease [170] Efficacy of anankinra in humans None
 Neurofibromatosis 1 NF1 mutations MEK inhibitor selumetinib 71% partial response rate for inoperable plexiform neurofibromas [92] FDA granted breakthrough status for selumetinib for NF1 in 2019 None
Hereditary and somatic mosaic conditions
 CLOVES syndrome Mosaic gain-of-function PIK3CA alterations Alpelisib, which is PIK3CA inhibitor Improved disease-related symptoms [113] Efficacy in humans Hormone-positive, HER2-negative breast cancer
 Central conducting lymphatic anomaly Gain-of-function ARAF mutations (MEK or mTOR pathway) Sirolimus (mTOR inhibitor) or trametinib (MEK inhibitor) Resolution of chylous output over the course of a week with removal of chest tube with sirolimus (n = 1) [53]
Dramatic clinical improvement, with remodeling of the patient’s lymphatic system and resolution of the lymphatic edema, marked improvement in pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities with trametinib (n = 1) [51]
Efficacy in humans Sirolimus: none
Trametinib: melanoma
 Fibroadipose hyperplasia PIK3CA mutations Sirolimus (mTOR inhibitor) Stabilization or improvement in disease in patients [115, 171] Efficacy in humans None
 Achondroplasia FGFR3 mutations FGFR3 inhibitor in mouse models Restored size of embryonic achrondroplastic femurs in animals [172] Animal model efficacy None