Table 2:

Preclinical Studies Demonstrating Some Evidence of Antagonism Between CDK4/6 Inhibitors and Chemotherapy

Author	Tumor Type	Context	Chemo	Outcome
Franco et al. Oncotarget 2014	Human PDA	In vitro	Gemcitabine 5FU	Observed antagonism when palbociclib was added to gemcitabine but cooperation between palbociclib and 5FU. Palbociclib reduced TS, the target of 5FU. Differential cell cycle sensitivity to palbociclib despite uniform suppression of RB phosphorylation.
McClendon et al. Cell Cycle 2012	Human TNBC	In vitro In vivo	Doxorubicin	In RB-proficient TNBC cell lines, co-treatment yielded cooperative cytostatic effects but reduced doxorubicin mediated cytotoxicity.
Dean et al. JBC 2012	Human TNBC	In vitro In vivo	Doxorubicin Paclitaxel Radiation	Mostly a biochemical demonstration that CDK4/6 inhibition blocks cells in G1 and is associated with reduced E2F gene expression even in the presence of chemotherapy. Pre-treatment and continuous palbociclib reduced paclitaxel effects in outgrowth assays, but pre and concurrent synchronization experiments enhanced activity in vivo. Showed CDK4/6 inhibition pushes DNA repair from HR to NHEJ and palbociclib leads to reduction of Ku70 needed for NHEJ, which implies that CDK4/6 inhibition may impair a cancer cells ability to repair chemotherapy induced DNA damage.
Roberts et al. JCI 2012	TNBC HER2	In vitro In vivo	Carboplatin Doxorubicin, Etoposide Camptothecin,Paclitaxel	Protection of “normal” cell line and bone marrow from chemotherapy. Concurrent palbociclib did not antagonize carboplatin in TNBC model. Concurrent palbociclib plus carboplatin treatment led to tumor regression in Her2 model, but depth of response was not as deep as single agent carboplatin.
Konecny et al. Clin Ca Re. 2011	Human Ovarian	In vitro	Carboplatin	Concurrent palbociclib treatment with carboplatin or paclitaxel resulted in synergism, however pre-treatment resulted in antagonism.
Cretella et al. Scientific Reports 2019	Human TNBC	In vitro	Paclitaxel	Pre-treatment with palbociclib sensitized cells to paclitaxel (sequential) and there was no difference in efficacy when paclitaxel was added 0, 4, 8 hours after palbociclib. Simultaneous treatment showed an antagonistic effect.