Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance
Abstract
:1. Role of HDAC6 in Cancer Cell Proliferation
2. Mechanism of HDAC6-Promoted Cancer Cell Proliferation
3. Roles of HDAC6-Targeting miRNAs in Cancer Cell Proliferation
4. HDAC6-Selective Inhibitors
5. Role of HDAC6 in Anti-Cancer Drug Resistance
6. Correlations between HDAC6 and PD-L1
7. Combination of HDAC6 Inhibition with Immune Check Point Blockade
8. Role of HDAC6 in Autophagy
9. Targeting Autophagy for Overcoming Anti-Cancer Drug Resistance
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Targets/Mechanism | Cancer Types | References |
---|---|---|
SMAD 2 phosphorylation ↓ P21 ↓ | Glioblastoma | [10] |
Binds to PTPN1 ERK1/2 activity ↑ Apoptosis ↓ | Melanoma | [18] |
HDAC6 ↓ MAPK/ERK ↓ | Colon Cancer | [19] |
MKK7 activity ↑ | Glioblastoma | [20] |
Oncogene EWSR1-FLI1 ↑ | Ewing Sarcoma | [21] |
RAC1 (Rho GTPase) activity ↑ | Rhabdomyosarcoma | [22] |
RAD51 ↑ CHEK activity ↑ | Glioblastoma | [23] |
Tumor suppressor MST1 ↓ | Breast Cancer | [24] |
P53 ↓ | Hepatocellular Carcinoma | [25] |
E-cadherin ↓ STAT activity ↑ | Breast Cancer | [26] |
C-Myc ↑ β-catenin Signaling ↑ | Colon Cancer | [27] |
miR-199 ↓ (negative regulator of Wnt signaling) | Cervical Carcinoma | [28] |
miRNAs | Mechanism | Cancer Types | References |
---|---|---|---|
miR-601 |
| Esophageal Squamous Cell Carcinoma | [37] |
miR-22 |
| Glioma | [39] |
miR-27b |
| Diffuse Large B-cell Lymphoma | [40] |
miR-206 |
| Endometrial Carcinoma | [43] |
mIR-433 |
| Cholangiocarcinoma | [46] |
HDAC6-Selective Inhibitor | Target/Mechanism | Enhances Sensitivity to | Cancer Types | References |
---|---|---|---|---|
WT161 | HDAC6 ↓ PTEN ↑ Apoptosis ↑ | 5-FU | Osteosarcoma | [53] |
WT-161 | HDAC6 ↓ EGFR/HER2/ERα ↓ | Bortezomib | Breast Cancer | [54] |
ACY-1215 (Ricolinostat) | HDAC6 ↓ Apoptosis ↑ | Gemcitabine and Oxaliplatin | Gallbladder Cancer | [60] |
ACY-1215 | HDAC6 ↓ Apoptosis ↑ | Gemcitabine | Pancreatic Ductal Adenocarcinoma | [61] |
ACY-1215 | HDAC6 ↓ Acetylation of α-tubulin ↑ | Eribulin | Breast Cancer | [62] |
ACY-1215 | HDAC6 ↓ Chk ↓ Mitotic catastrophe | Adavosertib | Head and Neck Squamous Cell Carcinoma | [63] |
A452 | HDAC6 ↓ ERK ↓ NF-κB ↓ | Bortezomib (BTZ) | Multiple Myeloma | [64] |
7b | HDAC6 ↓ BCR-ABL ↓ Leukemic stem cells ↓ | Imatinib | Chronic Myeloid Leukemia | [65] |
ACY-241 | HDAC6 ↓ | Paclitaxel | Advanced Solid Tumors | [66] |
HDAC6 Inhibitor | Enhances Sensitivity to | Mechanism | Cancer Types | References |
---|---|---|---|---|
Nexturastat | Anti-PD-1 antibody | CTL ↑ IL-1β/IL-6 ↓ PD-L1 ↓ | Non-Small Cell Lung Cancer | [76] |
XP-5 | Small molecule PD-L1 inhibitor | PD-L1 ↓ Tumor-Infiltrating Lymphocytes ↓ | Melanoma | [92] |
ACY1215 | Anti-PD-L1 antibody | IFN-γ positive CTL ↑ | Ovarian Cancer | [96] |
ACY738 | Anti-PD1 Anti-PD-L1 | CTL ↑ JAK/STAT ↓ IL-10 ↓ Acetylation of HSP90 ↑ | Chronic Lymphocytic Leukemia | [97] |
Nexturastat | Anti-PD-1 blockade | Pro-Tumorigenic M2 Macrophages ↓ Central/Memory T cells ↑ | Melanoma | [98] |
A542 | Immunomodulatory drugs (lenalidomide or pomalidomide) | AKT/ERK signaling ↓ | Multiple Myeloma | [99] |
Title | Inhibitors | Study Design | Types of Cancers | Phase | Study Dates | NCT Number |
---|---|---|---|---|---|---|
Safety, Tolerability, and MTD of KA2507 (HDAC6 inhibitor) | KA2507 |
| Solid Tumor, Adult | Phase 1 |
| NCT03008018 |
HDAC6 Inhibitor ACY-241 in Combination with Ipilimumab and Nivolumab | ACY-241, nivolumab, ipilimumab |
| Malignant Melanoma | Phase 1 (Stage III/Stage IV melanoma) |
| NCT02935790 |
HDAC6 Inhibitor KA2507 in Advanced Biliary Tract Cancer | KA2507 |
| Biliary Tract Cancer | Phase 2 |
| NCT04186156 |
ACY-241 in Combination with Nivolumab in Patients with Unresectable Non-Small Cell Lung Cancer | ACY-241, nivolumab |
| Non-Small Cell Lung Cancer | Phase 1 |
| NCT02635061 |
Orally Administered JBI-802, an LSD1/HDAC6 Inhibitor | JBI-802 |
| Locally Advanced Solid Tumor, Metastatic Solid Tumor | Phase 1 Phase 2 |
| NCT05268666 |
ACY-1215 Alone and in Combination With Bortezomib and Dexamethasone | ACY-1215 |
| Multiple Myeloma | Phase 1: To evaluate the side effects and determine the best dose of oral ACY-1215 as monotherapy, and in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. Phase 2: To determine the objective response rate of oral ACY-1215 in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma. |
| NCT01323751 |
ACY-1215 for Relapsed/Refractory Lymphoid Malignancies | ACY-1215 |
| Lymphoma, Lymphoid Malignancies | Phase 1: All patients will take the oral ACY-1215, 160 mg for 28 consecutive days on a 28-day treatment cycle Phase 2: All patients will take the oral ACY-1215, 160 mg for 28 consecutive days on a 28-day treatment cycle. |
| NCT02091063 |
ACY-1215+Nab-paclitaxel in Metastatic Breast Cancer | ACY-1215, Nab-paclitaxel |
An orally active, selective HDAC6 inhibitor
| Metastatic Breast Cancer, Breast Carcinoma | Phase 1 |
| NCT02632071 |
Safety, Pharmacokinetics, and Preliminary Antitumor Activity of ACY 241 in Combination with Paclitaxel in Patients With Advanced Solid Tumors | ACY-241 Paclitaxel |
② Paclitaxel: administered to patients at 80 mg/m2 IV over 1 h on Days 1, 8, and 15 of the 28-day treatment cycle
| Advanced solid tumors | Phase 1b |
| NCT02551185 |
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Jo, H.; Shim, K.; Jeoung, D. Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance. Int. J. Mol. Sci. 2022, 23, 9592. https://doi.org/10.3390/ijms23179592
Jo H, Shim K, Jeoung D. Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance. International Journal of Molecular Sciences. 2022; 23(17):9592. https://doi.org/10.3390/ijms23179592
Chicago/Turabian StyleJo, Hyein, Kyeonghee Shim, and Dooil Jeoung. 2022. "Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance" International Journal of Molecular Sciences 23, no. 17: 9592. https://doi.org/10.3390/ijms23179592
APA StyleJo, H., Shim, K., & Jeoung, D. (2022). Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance. International Journal of Molecular Sciences, 23(17), 9592. https://doi.org/10.3390/ijms23179592