Table 1.
Table summarizes the combination therapies comprising a CDK4/6-inhibitor plus another compound, tested in either clinical trials or preclinical models, described in the text.
| CDK-inhibitor | Combined with | Clinical Trial or Preclinical Moldel | Significance | Reference | |
|---|---|---|---|---|---|
| category | compound | ||||
| Palbociclib | aromatase inhibitor | Letrozole | PALOMA-2 (NCT01740427) | longer PFS respect to Letrozole alone | (7) |
| Palbociclib | SERD | Fulvestrant | PALOMA-3 (NCT01942135) | longer OS respect to Fulvestrant alone (not significant) | (47) |
| Ribociclib | aromatase inhibitor | Letrozole | MONALEESA-2 (NCT01958021) | longer PFS respect to Letrozole alone | (8) |
| Ribociclib | SERD | Fulvestrant | MONALEESA-3 (NCT02422615) | longer OS respect to Fulvestrant alone | (48) |
| Ribociclib | goserelin + aromatase inhibititor or Tamoxifen | MONALEESA-7 (NCT02278120) | longer OS respect to endocrine therapy alone | (49) | |
| Abemaciclib | SERD | Fulvestrant | MONARCH-2 (NCT02107703) | longer OS respect to Fulvestrant alone | (36) |
| Abemaciclib | aromatase inhibitor | Anastrozole or Letrozole | MONARCH-3 (NCT02246621) | longer PFS respect to aromatase inhibitor alone | (9) |
| Palbociclib | platinum compound | Carboplatin | ovarian cancer | DDR inhibition | (50) |
| Ribociclib | platinum compound | Cisplatin | ovarian cancer | DDR inhibition | (51) |
| Palbociclib | taxane | Taxol | pancreatic cancer | DNA-repair inhibition | (52) |
| Palbociclib | Wee-1 inhibitor | Adavosertib | sarcoma | mitotic catastrophe and senescence induction | (53) |
| Palbociclib | Wee-1 inhibitor | Adavosertib | HR+ breast cancer | apoptosis of G2 checkpoint dependent cells | (54) |
| Palbociclib | STAT3-inhibitor | Napabucasin | HR+ breast cancer | blockage of IL6/STAT3-induced resistance | (13) |
| Palbociclib | PRMT5-inhibitor | Pemrametostat | melanoma | restore of p53 activity | (55) |
| Palbociclib | MDM2-inhibitor | Nutlin-3 | melanoma | restore p53 and p21 expression | (56) |
| Palbociclib | Src-inhibitor | Saracatinib | colorectal cancer | reduce inhibitory phosphorylation of p27 | (57) |
| CDK6-silencing | Raf-inhibitor | Sorafenib | TN breast cancer | synthetic lethality due to synergistic interaction | (58) |
| Palbociclib, Ribociclib | MEK-inhibitor | Trametinib, U0126 | prostate cancer | revert MAPK-induced resistance to CDK-i | (59) |
| Ribociclib | PI3K-inhibitor | Alpelisib | TN breast cancer | reduce mTOR activity, increase anti-tumor T-cell response and immunotherapy sensitivity | (60) |
| Palbociclib | PI3K-inhibitor | Pictilisib (GDC-0941) | HR+ breast cancer | delay insurgence of CDK-i resistance | (23) |
| Palbociclib | mTOR-inhibitor | Vistusertib | HR+ breast cancer | delay insurgence of CDK-i resistance | (22) |
| Palbociclib | mTOR-inhibitor | Everolimus | glioblastoma | impact on cancer cell metabolism and improve CDK-i cytotoxicity | (24) |
| Abemaciclib | mTOR-inhibitor | Everolimus | HR+ breast cancer | inhibit cell growth of CDK-i resistant cells | (21) |
| Palbociclib | FGFR-inhibitor | FIIN-2, FIIN-3 | HR+ breast cancer | counteract FGFR-induced resistance | (61) |
| Palbociclib | pan-ERBB inhibitor | Afatinib | esophageal carcinoma | synthetic lethality due to synergistic interaction | (62) |
| Ribociclib | ALK-inhibitor | Ceritinib | neuroblastoma | synthetic lethality due to synergistic interaction | (63) |
| Palbociclib | Immunotherapy | anti-PD1-mAb | colon cancer model | synergistic interaction | (64) |
| Abemaciclib | Immunotherapy | anti-PDL1-Ab | mouse models | synergistic interaction | (65) |
| Palbociclib | autophagy-inhibitor | Hydroxychloroquine | HR+ breast cancer | synergistic interaction | (16) |
| Ribociclib | YAP-inhibitor | CA3 (CIL56) | esophageal carcinoma | induction of radiation sensitivity | (66) |
| Abemaciclib | YAP-inhibitor | Verteporfin | pancreatic cancer | synergistic interaction | (67) |
CDK-i, CDK4/6-inhibitors; DDR, DNA-damage response; HR, hormone receptor; mAb, monoclonal antibody; OS, overall survival; PFS, progression-free survival; SERD, selective estrogen receptor degrader; TN, triple-negative.