Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma.
Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce tolerance to MEK inhibitors, likely by decreasing the levels of cell death. Mechanistically, cIAP2 is upregulated at the transcript level in SOX10-deficient cells and the AP-1 complex protein, JUND, is required for its expression. Using a patient-derived xenograft model, we demonstrate that treatment with the cIAP1/2 inhibitor, birinapant, during the MRD phase delays the onset of resistance to BRAF inhibitor and MEK inhibitor combination therapy. Together, our data suggest that cIAP2 upregulation in SOX10-deficient subpopulations of melanoma cells induces drug tolerance to MAPK targeting agents and provides a rationale to test a novel therapeutical approach to target MRD.
Pubmed ID: 37343247 RIS Download
Research resources used in this publication
- NOD-scid IL2Rγnull (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) (RRID:BCBC_4142) (organism)
- Sox9 (D8G8H) Rabbit mAb #82630 (RRID:AB_2665492) (antibody)
- Wnt5a/b (C27E8) Rabbit mAb (RRID:AB_2215595) (antibody)
- PARP Antibody (RRID:AB_2160739) (antibody)
- HSP90 (C45G5) Rabbit mAb (RRID:AB_2233307) (antibody)
- Fra-2 (Q-20) (RRID:AB_2107084) (antibody)
- Anti-DFNA5/GSDME antibody [EPR19859] (RRID:AB_2737000) (antibody)
- Fra-2 (Q-20) (RRID:AB_2107084) (antibody)
- Sox10 (D5V9L) (RRID:AB_2792980) (antibody)
- Anti-DFNA5/GSDME antibody [EPR19859] (RRID:AB_2737000) (antibody)
- NOD-scid IL2Rγnull (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) (RRID:BCBC_4142) (organism)
- Goat Anti-Rabbit IgG, H & L Chain Specific Peroxidase Conjugate (RRID:AB_437787) (antibody)
- Sox10 (D5V9L) (RRID:AB_2792980) (antibody)
- Goat Anti-Mouse IgG, H&L Chain Specific Peroxidase Conjugate (RRID:AB_10682749) (antibody)
- NOD-scid IL2Rγnull (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) (RRID:BCBC_4142) (organism)
- cyclin A (B-8) (RRID:AB_10709300) (antibody)
- Goat Anti-Rabbit IgG, H & L Chain Specific Peroxidase Conjugate (RRID:AB_437787) (antibody)
- NFkappaB p65 (A) (RRID:AB_632039) (antibody)
- Goat Anti-Mouse IgG, H&L Chain Specific Peroxidase Conjugate (RRID:AB_10682749) (antibody)
- JUND-human (RRID:AB_2130177) (antibody)
- Anti-Actin antibody produced in rabbit (RRID:AB_476693) (antibody)
- cyclin A (B-8) (RRID:AB_10709300) (antibody)
- NFkappaB p65 (A) (RRID:AB_632039) (antibody)
- JUND-human (RRID:AB_2130177) (antibody)
- Recombinant Anti-Fibronectin antibody [F14] (RRID:AB_732380) (antibody)
- Anti-Actin antibody produced in rabbit (RRID:AB_476693) (antibody)
- Cleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (RRID:AB_2070042) (antibody)
- Recombinant Anti-Fibronectin antibody [F14] (RRID:AB_732380) (antibody)
- NF- B1 p105/p50 Antibody (RRID:AB_330564) (antibody)
- Cleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (RRID:AB_2070042) (antibody)
- p21 Waf1/Cip1 (12D1) Rabbit monoclonal antibody (RRID:AB_823586) (antibody)
- NF- B1 p105/p50 Antibody (RRID:AB_330564) (antibody)
- c-IAP1 (D5G9) Rabbit mAb (RRID:AB_10890862) (antibody)
- Cleaved PARP (Asp214) Antibody (Human Specific) (RRID:AB_331426) (antibody)
- p21 Waf1/Cip1 (12D1) Rabbit monoclonal antibody (RRID:AB_823586) (antibody)
- c-IAP1 (D5G9) Rabbit mAb (RRID:AB_10890862) (antibody)
- p44/42 MAPK (Erk1/2) Antibody (RRID:AB_330744) (antibody)
- Cleaved PARP (Asp214) Antibody (Human Specific) (RRID:AB_331426) (antibody)
- p44/42 MAPK (Erk1/2) Antibody (RRID:AB_330744) (antibody)
- Phospho-Rb (Ser807/811) Antibody (RRID:AB_331472) (antibody)
- V5-Tag (D3H8Q) Rabbit Antibody (RRID:AB_2687461) (antibody)
- c-IAP2 (58C7) Rabbit mAb (RRID:AB_10693298) (antibody)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Goat Anti-Rabbit IgG, H & L Chain Specific Peroxidase Conjugate (RRID:AB_437787)
- Goat Anti-Mouse IgG, H&L Chain Specific Peroxidase Conjugate (RRID:AB_10682749)
- Fra-2 (Q-20) (RRID:AB_2107084)
- cyclin A (B-8) (RRID:AB_10709300)
- Sox9 (D8G8H) Rabbit mAb #82630 (RRID:AB_2665492)
- NF- B1 p105/p50 Antibody (RRID:AB_330564)
- Wnt5a/b (C27E8) Rabbit mAb (RRID:AB_2215595)
- p21 Waf1/Cip1 (12D1) Rabbit monoclonal antibody (RRID:AB_823586)
- Phospho-Rb (Ser807/811) Antibody (RRID:AB_331472)
- HSP90 (C45G5) Rabbit mAb (RRID:AB_2233307)
- c-IAP2 (58C7) Rabbit mAb (RRID:AB_10693298)
- NFkappaB p65 (A) (RRID:AB_632039)
- Recombinant Anti-Fibronectin antibody [F14] (RRID:AB_732380)
- c-IAP1 (D5G9) Rabbit mAb (RRID:AB_10890862)
- V5-Tag (D3H8Q) Rabbit Antibody (RRID:AB_2687461)
- JUND-human (RRID:AB_2130177)
- Anti-Actin antibody produced in rabbit (RRID:AB_476693)
- Anti-DFNA5/GSDME antibody [EPR19859] (RRID:AB_2737000)
- Cleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (RRID:AB_2070042)
- Sox10 (D5V9L) (RRID:AB_2792980)
- PARP Antibody (RRID:AB_2160739)
- Cleaved PARP (Asp214) Antibody (Human Specific) (RRID:AB_331426)
- p44/42 MAPK (Erk1/2) Antibody (RRID:AB_330744)
Associated grants
- Agency: NCI NIH HHS, United States
Id: P30 CA010815 - Agency: NCI NIH HHS, United States
Id: T32 CA236736 - Agency: NCI NIH HHS, United States
Id: R01 CA160495 - Agency: NCI NIH HHS, United States
Id: P30 CA056036 - Agency: NCI NIH HHS, United States
Id: R01 CA182635 - Agency: NCI NIH HHS, United States
Id: P01 CA114046
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This is a list of tools and resources that we have found mentioned in this publication.
Goat Anti-Rabbit IgG, H & L Chain Specific Peroxidase Conjugate (antibody)
RRID:AB_437787
This unknown targets Goat Rabbit IgG H & L Chain Specific Peroxidase Conjugate
View all literature mentionsGoat Anti-Mouse IgG, H&L Chain Specific Peroxidase Conjugate (antibody)
RRID:AB_10682749
This polyclonal secondary targets IgG (H+L)
View all literature mentionscyclin A (B-8) (antibody)
RRID:AB_10709300
This monoclonal targets cyclin A (B-8)
View all literature mentionsSox9 (D8G8H) Rabbit mAb #82630 (antibody)
RRID:AB_2665492
This monoclonal targets Sox9
View all literature mentionsNF- B1 p105/p50 Antibody (antibody)
RRID:AB_330564
This polyclonal targets NF- B1 p105/p50
View all literature mentionsWnt5a/b (C27E8) Rabbit mAb (antibody)
RRID:AB_2215595
This monoclonal targets WNT5A
View all literature mentionsp21 Waf1/Cip1 (12D1) Rabbit monoclonal antibody (antibody)
RRID:AB_823586
This monoclonal targets p21 Waf1/Cip1
View all literature mentionsPhospho-Rb (Ser807/811) Antibody (antibody)
RRID:AB_331472
This polyclonal targets Phospho-Rb (Ser807/811)
View all literature mentionsHSP90 (C45G5) Rabbit mAb (antibody)
RRID:AB_2233307
This monoclonal targets Hsp90aa1
View all literature mentionsc-IAP2 (58C7) Rabbit mAb (antibody)
RRID:AB_10693298
This monoclonal targets c-IAP2
View all literature mentionsNFkappaB p65 (A) (antibody)
RRID:AB_632039
This polyclonal targets NFkappaB p65 (A)
View all literature mentionsRecombinant Anti-Fibronectin antibody [F14] (antibody)
RRID:AB_732380
This recombinant monoclonal targets Fibronectin
View all literature mentionsc-IAP1 (D5G9) Rabbit mAb (antibody)
RRID:AB_10890862
This monoclonal targets c-IAP1
View all literature mentionsV5-Tag (D3H8Q) Rabbit Antibody (antibody)
RRID:AB_2687461
This monoclonal targets V5-Tag
View all literature mentionsAnti-Actin antibody produced in rabbit (antibody)
RRID:AB_476693
This polyclonal targets Actin
View all literature mentionsAnti-DFNA5/GSDME antibody [EPR19859] (antibody)
RRID:AB_2737000
This monoclonal targets DFNA5/GSDME
View all literature mentionsCleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (antibody)
RRID:AB_2070042
This monoclonal targets Casp3
View all literature mentionsCleaved PARP (Asp214) Antibody (Human Specific) (antibody)
RRID:AB_331426
This polyclonal targets Cleaved PARP (Asp214) (Human Specific)
View all literature mentionsp44/42 MAPK (Erk1/2) Antibody (antibody)
RRID:AB_330744
This polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsNOD-scid IL2Rγnull (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) (organism)
RRID:BCBC_4142
View all literature mentions
Sox9 (D8G8H) Rabbit mAb #82630 (antibody)
RRID:AB_2665492
This monoclonal targets Sox9
View all literature mentionsWnt5a/b (C27E8) Rabbit mAb (antibody)
RRID:AB_2215595
This monoclonal targets WNT5A
View all literature mentionsHSP90 (C45G5) Rabbit mAb (antibody)
RRID:AB_2233307
This monoclonal targets Hsp90aa1
View all literature mentionsAnti-DFNA5/GSDME antibody [EPR19859] (antibody)
RRID:AB_2737000
This monoclonal targets DFNA5/GSDME
View all literature mentionsAnti-DFNA5/GSDME antibody [EPR19859] (antibody)
RRID:AB_2737000
This monoclonal targets DFNA5/GSDME
View all literature mentionsNOD-scid IL2Rγnull (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) (organism)
RRID:BCBC_4142
View all literature mentions
Goat Anti-Rabbit IgG, H & L Chain Specific Peroxidase Conjugate (antibody)
RRID:AB_437787
This unknown targets Goat Rabbit IgG H & L Chain Specific Peroxidase Conjugate
View all literature mentionsGoat Anti-Mouse IgG, H&L Chain Specific Peroxidase Conjugate (antibody)
RRID:AB_10682749
This polyclonal secondary targets IgG (H+L)
View all literature mentionsNOD-scid IL2Rγnull (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) (organism)
RRID:BCBC_4142
View all literature mentions
cyclin A (B-8) (antibody)
RRID:AB_10709300
This monoclonal targets cyclin A (B-8)
View all literature mentionsGoat Anti-Rabbit IgG, H & L Chain Specific Peroxidase Conjugate (antibody)
RRID:AB_437787
This unknown targets Goat Rabbit IgG H & L Chain Specific Peroxidase Conjugate
View all literature mentionsNFkappaB p65 (A) (antibody)
RRID:AB_632039
This polyclonal targets NFkappaB p65 (A)
View all literature mentionsGoat Anti-Mouse IgG, H&L Chain Specific Peroxidase Conjugate (antibody)
RRID:AB_10682749
This polyclonal secondary targets IgG (H+L)
View all literature mentionsAnti-Actin antibody produced in rabbit (antibody)
RRID:AB_476693
This polyclonal targets Actin
View all literature mentionscyclin A (B-8) (antibody)
RRID:AB_10709300
This monoclonal targets cyclin A (B-8)
View all literature mentionsNFkappaB p65 (A) (antibody)
RRID:AB_632039
This polyclonal targets NFkappaB p65 (A)
View all literature mentionsRecombinant Anti-Fibronectin antibody [F14] (antibody)
RRID:AB_732380
This recombinant monoclonal targets Fibronectin
View all literature mentionsAnti-Actin antibody produced in rabbit (antibody)
RRID:AB_476693
This polyclonal targets Actin
View all literature mentionsCleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (antibody)
RRID:AB_2070042
This monoclonal targets Casp3
View all literature mentionsRecombinant Anti-Fibronectin antibody [F14] (antibody)
RRID:AB_732380
This recombinant monoclonal targets Fibronectin
View all literature mentionsNF- B1 p105/p50 Antibody (antibody)
RRID:AB_330564
This polyclonal targets NF- B1 p105/p50
View all literature mentionsCleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb (antibody)
RRID:AB_2070042
This monoclonal targets Casp3
View all literature mentionsp21 Waf1/Cip1 (12D1) Rabbit monoclonal antibody (antibody)
RRID:AB_823586
This monoclonal targets p21 Waf1/Cip1
View all literature mentionsNF- B1 p105/p50 Antibody (antibody)
RRID:AB_330564
This polyclonal targets NF- B1 p105/p50
View all literature mentionsc-IAP1 (D5G9) Rabbit mAb (antibody)
RRID:AB_10890862
This monoclonal targets c-IAP1
View all literature mentionsCleaved PARP (Asp214) Antibody (Human Specific) (antibody)
RRID:AB_331426
This polyclonal targets Cleaved PARP (Asp214) (Human Specific)
View all literature mentionsp21 Waf1/Cip1 (12D1) Rabbit monoclonal antibody (antibody)
RRID:AB_823586
This monoclonal targets p21 Waf1/Cip1
View all literature mentionsc-IAP1 (D5G9) Rabbit mAb (antibody)
RRID:AB_10890862
This monoclonal targets c-IAP1
View all literature mentionsp44/42 MAPK (Erk1/2) Antibody (antibody)
RRID:AB_330744
This polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsCleaved PARP (Asp214) Antibody (Human Specific) (antibody)
RRID:AB_331426
This polyclonal targets Cleaved PARP (Asp214) (Human Specific)
View all literature mentionsp44/42 MAPK (Erk1/2) Antibody (antibody)
RRID:AB_330744
This polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsPhospho-Rb (Ser807/811) Antibody (antibody)
RRID:AB_331472
This polyclonal targets Phospho-Rb (Ser807/811)
View all literature mentionsV5-Tag (D3H8Q) Rabbit Antibody (antibody)
RRID:AB_2687461
This monoclonal targets V5-Tag
View all literature mentionsc-IAP2 (58C7) Rabbit mAb (antibody)
RRID:AB_10693298
This monoclonal targets c-IAP2
View all literature mentions
