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 | 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 |