Table 3.
Candidate Biomarkers of Imipridone Sensitivitya
| Candidate biomarkers of imipridone sensitivity | ||
|---|---|---|
| Biomarker | Effect on response | Ref. |
| Bim | Bim depletion impaired ONC201-induced apoptosis in myeloma cells | 29 |
| BIP | High expression of the ER chaperone BIP was associated with ONC201 and ONC212 resistance in pancreatic cancer cells | 9 |
| CLPP | • CLPP gene was essential for ONC201 and ONC212 sensitivity in leukemia cells | 11,17 |
| • CLPP D190A mutation abrogated response to ONC201 and ONC212 in AML and colorectal cancer cells; the mutation causes loss of the negative charge at ClpP’s active site and diminishes ONC201-ClpP binding affinity | ||
| • Pretreatment CLPP expression levels correlated to ONC201 sensitivity in AML primary samples | ||
| c-Myc | Higher c-Myc levels correlated to stronger apoptosis induction in ONC201, ONC206, and ONC212-treated glioblastoma cells | 10 |
| D(2) dopamine receptor (DRD2) | • High DRD2 expression was associated with ONC201 sensitivity in hepatocellular carcinoma cell lines | 3,13 |
| • Serum prolactin induction (indicative of D2R antagonism) was reported in most (n=22/25) patients receiving ONC201 | ||
| Dopamine receptor D5 (DRD5) | • DRD5 Knockdown increased ONC201 sensitivity in colorectal cancer cells, and pharmacological inhibition increased ONC201 sensitivity in neuroblastoma and glioblastoma (but not colorectal cancer) cells | 5,13,20 |
| • DRD5 overexpression or gain-of-function (Q366R mutation) reduced ONC201 sensitivity in glioblastoma cells | ||
| • DRD5 expression levels inversely correlated to ONC201 sensitivity, and low DRD5 expression correlated to improved clinical outcome in patients with glioblastoma | ||
| EGFR | • EGFR levels inversely correlated to ONC201 response, and ectopic expression of EGFR (constitutively active EGFRvIII) conferred ONC201 resistance in glioblastoma cell lines | 55 |
| • Low EGFR expression in pre-treatment clinical specimens correlated to improved progression free and overall survival outcomes among glioblastoma patients treated with ONC201 | ||
| GPR132 | High GPR132 levels correlated to increased ONC212 sensitivity in AML cells, independent of ISR induction | 12 |
| IGF1-R | High IGF1-R levels correlated to increased ONC201 and ONC212 sensitivity in pancreatic cancer cells | 9 |
| MIPEP | MIPEP gene was essential for ONC201 and ONC212 sensitivity in leukemia cells | 17 |
| mtDNA | • Reduced mitochondrial DNA (mtDNA) quantity was associated with ONC201 resistance in breast cancer cells | 10,27 |
| • mtDNA copy number decreased in ONC201-treated glioblastoma cells | ||
| mTOR | Knockdown or inactivating mutations were associated with increased ONC201 sensitivity in colorectal cancer cells | 56 |
| XIAP | Persistent levels of X-linked inhibitor of apoptosis (XIAP), which inhibits TRAIL, was associated with ONC201 resistance in colon cancer cells | 41 |
Abbreviations: ER AML, acute myeloid leukemia; EGFR, epidermal growth factor receptor MIPEP, mitochondrial intermediate peptidase; XIAP, X-linked inhibitor of apoptosis; mTOR, Mammalian Target of Rapamycin; BIP, binding immunoglobulin protein; CLPP, caseinolytic mitochondrial matrix peptidase proteolytic subunit.
aThe table lists examples of biomarkers that may be associated with imipridone sensitivity in various cancer types.