Table 2.
Epigenetic or transcriptomic causes of resistance to BRAF inhibitors (BRAFi) in melanoma
| Study | Mechanisms of resistance | Comment |
|---|---|---|
| Johannessen et al21 | Overexpression of MAP3K8 (also called COT) | COT overexpression drives resistance to BRAFi through MAPK-pathway reactivation COT activates ERK primarily through MEK-dependent mechanisms that do not require Raf signaling |
| Wily Hugo et al15 | Overexpression of cMet Underexpression of LEF1 and YAP1-signature enrichment |
Melanoma acquires MAPKi resistance with highly dynamic and recurrent nongenomic alterations and coevolving intratumoral immunity |
| Paraiso et al29 | Underexpression of BIM via PTEN loss | Loss of PTEN contributes to intrinsic BRAFi resistance via suppression of BIM-mediated apoptosis |
| Poulikakos et al22 | Expression of BRAFV600E-splicing variants | Expression of a BRAF splicing variant leads to structural change in BRAF and the ability of BRAFi to bind to it |
| Straussman et al19 | Stromal secretion of HGF | Proteomic analysis showed that stromal cell secretion of HGF resulted in activation of the HGF receptor Met, reactivation of the MAPK and PI3K–Akt signaling pathways, and immediate resistance to Raf inhibition in melanoma |
| Wily Hugo et al15 | Underexpression of CTLA4 Underexpression of antigen presentation genes (B2M, HLA-A, HLA-B, and TAP1) Underexpression of Wnt-signaling genes (LEF1, FZD6, WNT11, and WNT10A) Underexpression of RTK genes (AXL, EGFR, LK, NTRK2, and FGFR2) |
Transcriptomic underexpression accounted for the majority of highly recurrent LOF gene-based events in genes considered vital for active immunosurveillance in melanoma Gene- and signature-based transcriptomic alterations in acquired MAPKi-resistant melanoma highly recurrent |
| Sanchez-Laorden et al44 | cMet and IL8 overexpression | cMet and IL8 overexpressed in 44% and 40% of resistant tumors, respectively |
| Villanueva et al45 Nazarian et al23 |
Overexpression of PDGFRβ or IGF1R | |
| Shi et al25 Lidsky et al46 |
Overexpression of wild-type NRAS or KRAS | |
| Villanueva et al45 Nazarian et al23 |
RTK dysregulation | |
| van Allen et al20 Garraway et al47 |
MITF amplification | MITF amplification associated with resistance to MAPK inhibition; this gene encodes a master lineage transcription factor that governs melanocyte development and is also an amplified oncogene within the melanocyte lineage |
Abbreviation: LOF, loss of function.