Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?
Abstract
:1. Introduction
2. Treatment of Melanoma
3. Resistance Mechanisms to Targeted Therapy in Melanoma
3.1. Intrinsic Resistance
3.1.1. PI3K/AKT Pathway Activation
3.1.2. MAPK Pathway Activation
3.1.3. Disruptions to the Cell Cycle
3.2. Adaptive Resistance
3.2.1. ERK Signalling Reactivation
3.2.2. Alteration of Gene Transcription
3.2.3. Alteration of RTK Signalling
3.2.4. Metabolic Rewiring
3.3. Acquired Resistance
3.3.1. Secondary Mutations in the MAPK Pathway
3.3.2. Activation of Non-MAPK Proliferative Signalling
4. The Tumour Suppressor, RASSF1A
RASSF1A and Melanoma
5. Potential Impact of RASSF1A Loss on BRAFi Targeted Therapy Resistance
5.1. MAPK Pathway
5.2. PTEN Loss and PI3K/AKT Hyperactivation
5.3. RAC1 Hyperactivation
5.4. CCND1 Amplification and CDNK2A Loss
6. Restoration of RASSF1A Expression by Demethylating Agents
7. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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PATHWAY | GENE | ALTERATION | IMPLICATION | Intrinsic | Acquired | Res BRAFi | Res MEKi | Ref |
---|---|---|---|---|---|---|---|---|
Cell Cycle | CCND1 | High copy number | Increased expression | + | + | [41] | ||
CCND1 | Amplification | Increased expression | + | + | [42] | |||
CDK4 | K22Q, R24C/L | Activating mutation | + | − | [42] | |||
CDK4 | R24C/L | Activating mutation | +/− | +/− | +/− | +/− | [43] | |
CDKN2A | Low copy number | Low expression | + | + | [41] | |||
CDKN2A | D84N, M53T, N71fs | Inactivating mutation | + | +/− | + | [43] | ||
CDKN2A | deletion, truncation, missense mutation | Loss of function | +/− | +/− | +/− | +/− | [44] | |
MAPK | NRAS | Missense | Activating mutation | + | + | [45] | ||
NRAS | Q61 | Activating mutation | + | + | [46] | |||
NRAS | Q61K | Activating mutation | + | + | − | [47] | ||
CRAF | Increased levels | Increased MAPK signalling | + | + | [48] | |||
BRAFV600E | Amplification | Increased MAPK signalling | +/− | +/− | +/− | [44] | ||
BRAFV600E | High copy number | Increased MAPK signalling | + | + | − | [49] | ||
BRAFV600E | Amplification | Increased MAPK signalling | + | + | [45] | |||
BRAFV600E | Splice variant (p61BRAFV600E) | Increased MAPK signalling | + | + | [50] | |||
MAP2K1 | P124SQ/S | Activating mutation | + | + | + | [51] | ||
MAP2K1 | P124S | Activating mutation | +/− | +/− | [44] | |||
MAP2K1 | Q56P | Activating mutation | +/− | +/− | [44] | |||
MAP2K1 | Q56P, E203K | Activating mutation | + | + | [46] | |||
MAP2K1 | P124L | Activating mutation | + | + | [43] | |||
MAP2K1 | V60E, G128V, V154I | Activating mutation | + | + | [45] | |||
MAP2K1 | P124S/L | Activating mutation | + | + | [45] | |||
MAP2K2 | V35M, L46F, C125S N126D | Activating mutation | + | + | [45] | |||
MAP2K2 | W251Ter, A182V | + | +/− | + | [43] | |||
NF1 | X2441_splice | Loss of expression | + | + | [44] | |||
NF1 | Gln282fs, Arg440 * | Loss of function | − | [52] | ||||
NF1 | P195S | + | +/− | [43] | ||||
MAP3K8 (COT) | Increased levels | Increased ERK signalling | + | + | + | + | [53] | |
RTK | EGFR | Amplification, R451C | Increased activity | + | +/− | +/− | +/− | [43] |
EGFR | Demethylation of EGFR regulatory DNA elements | Increased PI3K/AKT signalling | + | + | [54] | |||
IGF-1R | Increased levels | Increased PI3K/AKT signalling | + | + | − | [55] | ||
AXL | Increased levels | + | + | + | + | [56] | ||
KIT | Amplification, G498S | Increased activity | + | +/− | + | + | [43] | |
PDGFRβ | Increased levels | Independent MAPK-pro-survival | + | + | [47] | |||
SOX10 | Low levels | Increased RTK | − | + | + | [57] | ||
T. microenvironment | HGF | Stromal secretion | Activation of MET | + | + | [58] | ||
PI3K/AKT | PIK3CA | V344G, E545K, H1047R | Activating mutation | +/− | +/− | [44] | ||
PIK3CA | missense | + | + | + | [45] | |||
PTEN | mutation, deletion | Loss of function | +/− | +/− | [41] | |||
PTEN | missense mutation, indel | Loss of function | + | + | [45] | |||
PTEN | missense mutation, non-sense mutation, deletion, indel | Loss of function | + | + | [45] | |||
PTEN | Loss/deletion, splice, T27C, P244fs | Loss of function | + | + | +/− | +/− | [43] | |
PTEN | deletions, truncation, missense mutation | Loss of function | + | + | + | [44] | ||
Small GTPases (other than RAS) | RAC | P29S | Activating mutation | + | + | [59] | ||
RAC | P29S | Activating mutation | + | + | [60] | |||
RAC | P29S/L | Activating mutation | + | + | + | [61] | ||
RAC | P29S | Activating mutation | + | + | + | [43] | ||
RAC | P29S | Activating mutation | + | [62] | ||||
RAC | P29S | Activating mutation | + | + | [45] | |||
Metabolic rewiring | MITF | Amplification | Increased activity | + | + | + | [45] | |
MITF | Amplifications, G6R, R316K, S502F | Increased activity | + | +/− | +/− | − | [43] |
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McKenna, S.; García-Gutiérrez, L. Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing? Int. J. Mol. Sci. 2021, 22, 5115. https://doi.org/10.3390/ijms22105115
McKenna S, García-Gutiérrez L. Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing? International Journal of Molecular Sciences. 2021; 22(10):5115. https://doi.org/10.3390/ijms22105115
Chicago/Turabian StyleMcKenna, Stephanie, and Lucía García-Gutiérrez. 2021. "Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing?" International Journal of Molecular Sciences 22, no. 10: 5115. https://doi.org/10.3390/ijms22105115