Table 1.
Summary of preclinical studies using combinatorial therapies.
| Thyroid Cancer Type | Cell Line | Species | Mutation | Molecular Target | Combination of Therapies | References |
|---|---|---|---|---|---|---|
| Anaplastic form | SW1736 | Human | Heterozygous BRAFV600E, Heterozygous for TERT c.228C >T (-124C >T), Homozygous for TP53 p.Gln192Ter, Heterozygous for TSHR p.Ile486Phe | BRAFV600E inhibitor/proteasome inhibitor | Vemurafenib + Bortezomib | Tsumagari et al., 2018 |
| MEK1/2 inhibitor/mTOR inhibitor | RDEA119 + temsirolimus | Liu et al., 2010 | ||||
| Raf inhibitor/immunotherapy | PLX4720 + anti PDL-1 | Brauner et al., 2015 | ||||
| Withanolide (potent of heat-shock protein inhibition)/VEGF inhibitor | Withaferin A + Sorafenib | Cohen et al., 2012 | ||||
| Selective inhibitor of nuclear export/chemotherapy | Selinexor + doxorubicin | Garg et al., 2017 | ||||
| mTOR inhibitor/chemotherapy | AZD2014 + paclitaxel | Milošević et al., 2018 | ||||
| Histone deacetylase inhibitor/chemotherapy | Suberoylanilide hydroxamic acid (SAHA) + docetaxel | Pozdeyev et al., 2015 | ||||
| KAT 18 | Human | Heterozygous for MRE11A p.Leu57Ter, Heterozygous for TERT c.228C >T (−124C >T), Homozygous for TP53 p.Gly199Val (c.596G >T) | BRAFV600E inhibitor/proteasome inhibitor | Vemurafenib + Bortezomib | Tsumagari et al., 2018 | |
| MEK1/2 inhibitor/mTOR inhibitor | RDEA119 + temsirolimus | Liu et al., 2010 | ||||
| KAT 4 | Human | Heterozygous for APC p.Glu853Ter (c.2557G >T) and p.Thr1556fs*3 (c.4666_4667insA), Heterozygous for BRAF p.Val600Glu (c.1799T >A), Heterozygous for PIK3CA p.Pro449Thr (c.1345C >A), Homozygous for SMAD4 p.Gln311Ter (c.931C >T), Homozygous for TP53 p.Arg273His (c.818G >A) | AKT inhibitor/platelet-derived growth factor receptor inhibitor | MK-2206 + tyrphotsin AG 1296 | Che et al., 2014 | |
| MEK1/2 inhibitor/VEGF inhibitor | SL327 + sunitinib | Wang et al., 2017 | ||||
| 8505c | Human | Homozygous for BRAF p.Val600Glu, Homozygous for NF2 p.Glu129Ter, Heterozygous for TERT c.250C >T, Homozygous for TP53 p.Arg248Gly | Bcl2 family inhibitor/MAPK inhibitors | ABT-737 + PLX4720 + PD32590 | Gunda et al., 2017 | |
| SRC inhibitor/Raf inhibitor | Dasatinib + PLX4720 | Vanden Borre et al., 2014 | ||||
| Flavonoid derivative/BRAFV600E inhibitor/PI3K inhibitor | Apigenin + vemurafenib + wortmannin | Kim et al., 2013 | ||||
| Raf inhibitor/immunotherapy | PLX4720 + anti PDL-1 | Brauner et al., 2015 | ||||
| Raf inhibitor/PI3K inhibitor | RAF265 + Dactolisib (BEZ-235) | Jin et al., 2011 | ||||
| Growth factor inhibition/AKT inhibitor | shRNA TGF-β1 + MK-2206 | Li et al., 2016 | ||||
| BRAFV600E inhibitor/c-Met inhibitor | Vemurafenib + PHA665752 | Byeon et al., 2017 | ||||
| Mek inhibitor/PI3K inhibitor | PD-325901 + GDC-0941 | ElMokh et al., 2017 | ||||
| VEGF inhibitor/PI3K inhibitor/AKT inhibition | Sorafenib + Dactolisib (BEZ235)/small interfering RNA (siRNA) directed against AKT | Yi H et al.,2017 | ||||
| VEGF inhibitor/antimalaria drug | Sorafenib + Quinacrine | Abdulghani et al., 2016 | ||||
| VEGF inhibitor/antimalaria drug | Sorafenib + chloroquine | Yi H et al.,2018 | ||||
| VEGF inhibitor/Histone deacetylase inhibitor | Sorafenib + N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA) | Cheong Park et al., 2017 | ||||
| anti parasitic drug/chemotherapy | Atovaquone + Doxorubicin | Zhuo Lv et al., 2018 | ||||
| Oxidized tetracyclic triterpenoids (inhibitor JAK/STAT)/chemotherapy |
Cucurbitacin B + Doxorubicin | Hyoung Kim et al., 2017 | ||||
| mTOR inhibitor/chemotherapy | AZD2014 + paclitaxel | Milošević et al., 2018 | ||||
| Antibiotic/Chemotherapy | Tanespimycine (17-allylamino-17-demethoxygeldanamycin) + paclitaxel | Kim et al., 2014 | ||||
| Bioactive flavone/chemotherapy | Baicalein + docetaxel | Ho Park et al., 2018 | ||||
| Histone deacetylase inhibitor/chemotherapy | Suberoylanilide hydroxamic acid (SAHA) + docetaxel | Pozdeyev et al., 2015 | ||||
| VEGF inhibitor/chemotherapy | Lenvatinib + Paclitaxel | Jing et al., 2017 | ||||
| BRAF inhibitor/TKI | Vemurafenib + Ponatinib | Ghosh et al., 2020 | ||||
| MEK inhibitor/dietary supplement | U0126 + sodium selenite | Kim et al., 2020 | ||||
| HTh-7 | Human | NRAS p.Gln61Arg (c.182A >G), KMT2D p.Gln4118Ter, Homozygous for TERT c.250C >T, TP53 p.Gly245Ser | Bcl2 family inhibitor/MAPK inhibitors | ABT-737 + PLX4720 + PD32590 | Gunda et al., 2017 | |
| Raf inhibitor/immunotherapy | PLX4720 + anti PDL-1 | Brauner et al., 2015 | ||||
| Selective inhibitor of nuclear export/chemotherapy | Selinexor + doxorubicin | Garg et al., 2017 | ||||
| TBP-3743 | Murine | BrafV600E/WT; p53/ | SRC inhibitor/Raf inhibitor | Dasatinib + PLX4720 | Vanden Borre et al., 2014 | |
| Immunotherapy/VEGF inhibitor | Anti PDL1 + lenvatinib | Gunda et al., 2019 | ||||
| TBPt-3403 | Murine | BrafV600E/WT; Pten−/− | SRC inhibitor/Raf inhibitor | Dasatinib + PLX4720 | Vanden Borre et al., 2014 | |
| TBPt-3610R | Murine | BrafV600E/WT; Pten−/− | SRC inhibitor/Raf inhibitor | Dasatinib + PLX4720 | Vanden Borre et al., 2014 | |
| FRO | Human | Heterozygous BRAFV600E mutation | Flavonoid derivative/BRAFV600E inhibitor/PI3K inhibitor | Apigenin + vemurafenib + wortmannin | Kim et al., 2013 | |
| VEGF inhibitor/chemotherapy | Pazopanib + Paclitaxel | Isham et al., 2013 | ||||
| ACT-1 | Human | Heterozygous for NRAS p.Gln61Lys, Heterozygous for TERT c.250C >T, Homozygous for TP53 p.Cys242Ser | MAPK inhibitors | Trametinib + dabrafenib | Kurata et al., 2016 | |
| OCUT-1 | Human | Heterozygous for BRAF p.Val600Glu (c.1799T >A), Heterozygous for TERT c.228C >T (-124C >T), Homozygous for TERT c.250C >T | MEK1/2 inhibitor/mTOR inhibitor | RDEA119 + temsirolimus | Liu et al., 2010 | |
| AKT inhibitor/MEK inhibitor | MK-2206 + selumetinib | Liu et al., 2012 | ||||
| OCUT-2 | Human | Heterozygous for BRAF p.Val600Glu, Homozygous for TERT c.250C >T | MAPK inhibitors | Trametinib + dabrafenib | Kurata et al., 2016 | |
| OCUT-4 | Human | BRAF and PI3KCA mutations | MAPK inhibitors | Trametinib + dabrafenib | Kurata et al., 2016 | |
| OCUT-6 | Human | Wildtype BRAF and NRAS mutations | MAPK inhibitors | Trametinib + dabrafenib | Kurata et al., 2016 | |
| THJ-11T | Human | KRAS p.Gly12Val (c.35G >T), Heterozygous for TERT c.228C >T | MEK inhibitor/BET inhibitor | Trametinib + JQ1 | Zhu et al., 2018 | |
| VEGF inhibitor/chemotherapy | Pazopanib + Paclitaxel | Isham et al., 2013 | ||||
| THJ-16T | Human | MKRN1-BRAF in-frame gene fusion, Heterozygous for PIK3CA p.Glu545Lys, Homozygous for EP300 p.Ser799Phefs*5, Heterozygous for RET p.Glu90Lys, Heterozygous for TERT c.228C >T, Homozygous for TP53 p.Arg273His | MEK inhibitor/BET inhibitor | Trametinib + JQ1 | Zhu et al., 2018 | |
| PI3K inhibitor/p53 reactivator | NVP-BKM120 + PRIMA-1Met | Li et al., 2018 | ||||
| VEGF inhibitor/antimalaria drug | Sorafenib + Quinacrine | Abdulghani et al., 2016 | ||||
| Histone deacetylase inhibitor + chemotherapy | Suberoylanilide hydroxamic acid (SAHA) + docetaxel | Pozdeyev et al., 2015 | ||||
| VEGF inhibitor/chemotherapy | Pazopanib + Paclitaxel | Isham et al., 2013 | ||||
| BRAF inhibitor + TKI | Vemurafenib + Ponatinib | Ghosh et al., 2020 | ||||
| THJ-21T | Human | Homozygous for BRAF p.Val600Glu (c.1799T >A), Heterozygous for TERT c.228C >T (-124C >T); in promoter, Homozygous for TP53 p.Arg280Thr (c.839G >C) | PI3K inhibitor/p53 reactivator | NVP-BKM120 + PRIMA-1Met | Li et al., 2018 | |
| VEGF inhibitor/antimalaria drug | Sorafenib + Quinacrine | Abdulghani et al., 2016 | ||||
| VEGF inhibitor/chemotherapy | Pazopanib + Paclitaxel | Isham et al., 2013 | ||||
| THJ-29T | Human | FGFR2-OGDH in-frame gene fusion, Homozygous for CDKN2A p.Gln70Serfs*102 (c.207delG) (G55fs), Heterozygous for HDAC10 p.His134Thrfs*19 (c.399delG), Heterozygous for TERT c.250C >T (-146C >T); in promoter, Homozygous for TP53 p.Gln104Ter (c.310C >T) | PI3K inhibitor/p53 reactivator | NVP-BKM120 + PRIMA-1Met | Li et al., 2018 | |
| VEGF inhibitor/antimalaria drug | Sorafenib + Quinacrine | Abdulghani et al., 2016 | ||||
| VEGF inhibitor/chemotherapy | Pazopanib + Paclitaxel | Isham et al., 2013 | ||||
| Hth-74 | Human | Homozygous for NF1 p.Leu732fs (c.2195_2202delTGCCCAAC), Homozygous for TERT c.228C >T (-124C >T) | PI3K inhibitor/p53 reactivator | NVP-BKM120 + PRIMA-1Met | Li et al., 2018 | |
| VEGF inhibitor/anti diabetic drug | Sorafenib + metformin | Chen et al., 2015 | ||||
| Selective inhibitor of nuclear export/chemotherapy | Selinexor + doxorubicin | Garg et al., 2017 | ||||
| ARO | Human | Heterozygous for APC p.Glu853Ter (c.2557G >T), Thr1556fs*3 (c.4666_4667insA), Heterozygous for BRAF p.Val600Glu (c.1799T >A), Heterozygous for PIK3CA p.Pro449Thr (c.1345C >A), Homozygous for SMAD4 p.Gln311Ter (c.931C >T), Homozygous for TP53 p.Arg273His (c.818G >A) | Ras inhibitor/galectin 3 inhibitor | Transfarnesylthiosalicylic acid (FTS) + Modified citrus pectin (MCP) | Menachem et al., 2015 | |
| HTOR | Human | X-Normal thyroid cells | Raf inhibitor/immunotherapy | PLX4720 + anti PDL-1 | Brauner et al., 2015 | |
| PI3K inhibitor/p53 reactivator | NVP-BKM120 + PRIMA-1Met | Li et al., 2018 | ||||
| CAL-62 | Human | Heterozygous for CREBBP p.Glu1541Ter (c.4621G >T), Homozygous for EP300 p.Asp1485fs (c.4454delA), Homozygous for KRAS p.Gly12Arg (c.34G >C), Homozygous for NF2 p.Glu215Ter (c.643G >T), Homozygous for TP53 p.Ala161Asp (c.482C >A) | Raf inhibitor/PI3K inhibitor | RAF265 + Dactolisib (BEZ-235) | Jin et al., 2011 | |
| AKT inhibitor/platelet-derived growth factor receptor inhibitor | MK-2206 + tyrphotsin AG 1296 | Che et al., 2014 | ||||
| Oxidized tetracyclic triterpenoids (inhibitor JAK/STAT)/chemotherapy |
Cucurbitacin B + doxorubicin | Hyoung Kim et al., 2017 | ||||
| Selective inhibitor of nuclear export/chemotherapy | Selinexor + doxorubicin | Garg et al., 2017 | ||||
| MEK inhibitor/VEGF inhibitor | SL327 + sunitinib | Wang et al., 2017 | ||||
| Antibiotic/Chemotherapy | Tanespimycine (17-allylamino-17-demethoxygeldanamycin) + paclitaxel | Kim et al., 2014 | ||||
| C643 | Human | HRAS p.Gly13Arg (c.37G >C), Heterozygous for PTEN p.Phe341Leu (c.1023T >G), Heterozygous for TERT c.228C >T (-124C >T), Homozygous for TP53 p.Arg248Gln (c.743G >A), VTCN1 p.Tyr215Ter (c.645C >G) | Raf inhibitor/PI3K inhibitor | RAF265 + BEZ-235 | Jin et al., 2011 | |
| VEGF inhibitor/chemotherapy | Lenvatinib + Paclitaxel | Jing et al., 2017 | ||||
| BRAF inhibitor/TKI | Vemurafenib + Ponatinib | Ghosh et al., 2020 | ||||
| SNU-80 | Human | BRAF p.Gly469Arg (c.1405G >C), Heterozygous for TP53 p.Pro278Ala (c.832C >G) | Histone deacetylase inhibitor/VEGF inhibitor | N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA) + Sorafenib | Cheong Park et al., 2017 | |
| GSA1 | Human | X | Histone deacetylase inhibitor/VEGF inhibitor | N-hydroxy-7-(2-naphthylthio) hepatonomide (HNHA) + Sorafenib | Cheong Park et al., 2017 | |
| T238 | Human | BRAF p.Val600Glu (c.1799T >A),Homozygous for CDKN2A p.Leu63Arg (c.188T >G),Heterozygous for PIK3CA p.Glu542Lys (c.1624G >A),Heterozygous for TERT c.228C >T (-124C >T),Homozygous for TP53 p.Ser183Ter (c.548C >G) | Selective inhibitor of nuclear export/chemotherapy | Selinexor + doxorubicin | Garg et al., 2017 | |
| Hth-83 | Human | Homozygous for AR p.Gly456_Gly457insGly (c.1368_1369insGGA), Heterozygous for HRAS p.Gln61Arg (c.182A >G),Heterozygous for TERT c.228C >T (-124C >T),Heterozygous for TP53 p.Pro153Alafs*28 | Selective inhibitor of nuclear export/chemotherapy | Selinexor + doxorubicin | Garg et al., 2017 | |
| 8305C | Human | Heterozygous for ATM p.Gln2800Ter (c.8398C >T),Heterozygous for BRAF p.Val600Glu (c.1799T >A),Heterozygous for NRAS p.Phe90fs (c.270delT),Homozygous for TP53 p.Arg273Cys (c.817C >T),Heterozygous for TERT c.250C >T (-146C >T) | Chemotherapy/VEGF inhibitor | Irinotecan + sunitinib | Di Desidero et al., 2017 | |
| VEGF inhibitor/chemotherapy | Lenvatinib + Paclitaxel | Jing et al., 2017 | ||||
| FB3 | Human | X | Chemotherapy/VEGF inhibitor | Irinotecan + sunitinib | Di Desidero et al., 2017 | |
| KTC-1 | Human | Heterozygous for BRAF p.Val600Glu, Heterozygous for RAC1 p.Asp63Val, Heterozygous for TERT c.250C >T | VEGF inhibitor/chemotherapy | Pazopanib + Paclitaxel | Isham et al., 2013 | |
| KTC-2 | Human | Heterozygous for BRAF p.Val600Glu (c.1799T >A),Heterozygous for KMT2D p.Glu490Ter (c.1468G >T),Heterozygous for TERT c.228C >T (-124C >T) | VEGF inhibitor/chemotherapy | Pazopanib + Paclitaxel | Isham et al., 2013 | |
| KTC-3 | Human | X | VEGF inhibitor/chemotherapy | Pazopanib + Paclitaxel | Isham et al., 2013 | |
| Papillary form | BCPAP | Human | Homozygous for BRAF p.Val600Glu, Heterozygous for TERT c.228C >T, Homozygous for TP53 p.Asp259Tyr | MEK inhibitor/VEGF inhibitor | Dabrafenib/selumetinib + lapatinib | Cheng et al.,2017 |
| Bcl2 family inhibitor/MAPK inhibitors | ABT-737 + PLX4720 + PD32590 | Gunda et al., 2017 | ||||
| SRC inhibitor/Raf inhibitor | Dasatinib + PLX4720 | Vanden Borre et al., 2014 | ||||
| MEK1/2 inhibitor/mTOR inhibitor | RDEA119 + temsirolimus | Liu et al., 2010 | ||||
| Raf inhibitor/immunotherapy | PLX4720 + anti PDL-1 | Brauner et al., 2015 | ||||
| Raf inhibitor/PI3K inhibitor | RAF265 + Dactolisib (BEZ-235) | Jin et al., 2011 | ||||
| PI3K inhibitor/p53 reactivator | NVP-BKM120 + PRIMA-1Met | Li et al., 2018 | ||||
| BRAFV600E inhibitor/c-met inhibitor | PLX4032 + PHA665752 | Byeon et al., 2017 | ||||
| Natural withanolide/VEGF inhibitor | Withaferin A + Sorafenib | Cohen et al., 2012 | ||||
| Histone deacetylase inhibitor + chemotherapy | Suberoylanilide hydroxamic acid (SAHA) + docetaxel | Pozdeyev et al., 2015 | ||||
| BRAF inhibitor/TKI | Vemurafenib + Ponatinib | Ghosh et al., 2020 | ||||
| BRAF inhibitor/EZH2 inhibitor | Selumetinib/dabrafenib + tazemetostat | Fu et al., 2020 | ||||
| K1 | Human | Heterozygous for BRAF p.Val600Glu, Heterozygous for PIK3CA p.Glu542Lys, Heterozygous for TERT c.228C >T | MEK inhibitor/VEGF inhibitor | Dabrafenib/selumetinib + lapatinib | Cheng et al.,2017 | |
| AKT inhibitor/MEK inhibitor | MK-2206 + selumetinib | Liu et al., 2012 | ||||
| BRAF inhibitor/EZH2 inhibitor | Selumetinib/dabrafenib + tazemetostat | Fu et al., 2020 | ||||
| BHP 2-7 | Human | CCDC6-RET (RET/PTC1) gene fusion, Homozygous for CDKN2A p.Ala68fs, Heterozygous for STAG2 p.Gln1089Ter, Heterozygous for TERT c.228C >T | MEK inhibitor/VEGF inhibitor | Dabrafenib/selumetinib + lapatinib | Cheng et al.,2017 | |
| TPC-1 | Human | CCDC6-RET (RET/PTC1) gene fusion, Homozygous for CDKN2A p.Ala68fs, Heterozygous for STAG2 p.Gln1089Ter, Heterozygous for TERT c.228C >T | Bcl2 family inhibitor/MAPK inhibitors | ABT-737 + PLX4720 + PD32590 | Gunda et al., 2017 | |
| Raf inhibitor/immunotherapy | PLX4720 + anti PDL-1 | Brauner et al., 2015 | ||||
| MEK inhibitor/dietary supplement | U0126 + sodium selenite | Kim et al., 2020 | ||||
| BRAF inhibitor + EZH2 inhibitor | Selumetinib/dabrafenib + tazemetostat | Fu et al., 2020 | ||||
| TBP-3868 | Murine | BrafV600E/WT; p53−/− | SRC inhibitor/Raf inhibitor | Dasatinib + PLX4720 | Vanden Borre et al., 2014 | |
| Follicular form | FTC-133 | Human | Homozygous for FLCN p.His429fs (c.1285delC), Homozygous for MSH6 p.Lys1045fs (c.3135delG),Homozygous for NF1 p.Cys167Ter (c.501T >A), Homozygous for PTEN p.Arg130Ter (c.388C >T), Homozygous for TERT c.228C >T (-124C >T), Homozygous for TP53 p.Arg273His (c.818G >A) | MEK1/2 inhibitor/mTOR inhibitor | RDEA119 + temsirolimus | Liu et al., 2010 |
| Raf inhibitor/PI3K inhibitor | RAF265 + Dactolisib (BEZ-235) | Jin et al., 2011 | ||||
| PI3K inhibitor/p53 reactivator | NVP-BKM120 + PRIMA-1Met | Li et al., 2018 | ||||
| VEGF inhibitor/PI3K inhibitors | Sorafenib+ Dactolisib (BEZ235)/small interfering RNA (siRNA) directed against AKT | Yi H et al.,2017 | ||||
| VEGF inhibitor/spice | Sorafenib + curcumin | Zhang et al., 2015 | ||||
| VEGF inhibitor/antimalaric drug | Sorafenib + chloroquine | Yi H et al.,2018 | ||||
| anti parasitic drug/chemotherapy | Atovaquone + Doxorubicin | Zhuo Lv et al., 2018 | ||||
| WRO-82-1 | Human | BRAF p.Val600Glu (c.1799T >A), TP53 p.Pro223Leu (c.668C >T) | MEK1/2 inhibitor/mTOR inhibitor | RDEA119 + temsirolimus | Liu et al., 2010 | |
| VEGF inhibitor/chemotherapy | Pazopanib + Paclitaxel | Isham et al., 2013 | ||||
| Medullary form | TT | Human | Heterozygous for RET p.Cys634Trp (c.1902C >G), Heterozygous for TBX3 p.Trp197Ter (c.591G >A) | PI3K inhibitor/Raf inhibitor | ZSTK474+ RAF265 | Bertazza et al., 2015 |
| VEGF inhibitor/MEK inhibitor- mTOR inhibitor/MEK inhibitor | Sorafenib + AZD6244/Everolimus + AZD6244 | Koh et al., 2012 | ||||
| MZ-CRC-1 | Human | Heterozygous for HIST3H3 p.Arg3Ter (c.7C >T),Homozygous for MAX c.295+1G >A, Homozygous for PBRM1 p.Arg534Ter (c.1600C >T),Heterozygous for RET p.Met918Thr (c.2753T >C) | VEGF inhibitor/MEK inhibitor- mTOR inhibitor/MEK inhibitor | Sorafenib + AZD6244/Everolimus + AZD6244 | Koh et al., 2012 | |
| VEGF inhibitor/chemotherapy | Sunitinib + cisplatin | Lopergolo et al., 2014 |