Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and limit therapeutic response. While CDK4/6 represents a downstream target of both KRAS mutation and loss of the CDKN2A tumor suppressor in PDAC, clinical and preclinical studies indicate that pharmacological CDK4/6 inhibitors are only modestly effective. Since chemotherapy represents the established backbone of PDAC treatment we evaluated the interaction of CDK4/6 inhibitors with gemcitabine and taxanes that are employed in the treatment of PDAC. Herein, we demonstrate that the difference in mechanisms of actions of chemotherapeutic agents elicit distinct effects on the cellular response to CDK4/6 inhibition. Gemcitabine largely ablates the function of CDK4/6 inhibition in S-phase arrested cells when administered contemporaneously; although, when cells recover from S-phase block they exhibit sensitivity to CDK4/6 inhibition. In contrast, pharmacological inhibition of CDK4/6 yields a cooperative cytostatic effect in combination with docetaxel and prevents adaptation and cell cycle re-entry, which is a common basis for resistance to such agents. Importantly, using organoid and PDX models we could confirm the cooperative effects between chemotherapy and CDK4/6 inhibition. These data indicate that the combination of cytotoxic and cytostatic agents could represent an important modality in those tumor types that are relatively resistant to CDK4/6 inhibitors. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

“…CDK, which is one of the most critical molecules for several cell cycle transitions, has recently been considered a key target to treat ER-positive breast cancer. Indeed, the results of recent clinical trials indicate that combinations of cell cycle inhibitors and other drugs may be one of the most promising therapeutic approaches to breast cancer in the future [6,[34][35][36][37][38]. To this end, we cannot help but speculate that the G2M pathway score may have a utility to be used for patient selection and as a predictive biomarker for CDK inhibitors among patients with ER-positive breast cancer.…”

The E2F Pathway Score as a Predictive Biomarker of Response to Neoadjuvant Therapy in ER+/HER2− Breast Cancer

“…Our group and others have reported that tumor immune microenvironment (TIME) is deeply involved in cancer progression in multiple settings [ 58 , 59 , 60 ]. Cell cycle activity was recently reported to correlate with increased anti-tumor immunity in multiple cancers [ 61 ], and CDK4/6 inhibition was reported to trigger anti-cancerous immunity [ 62 ].…”

Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition

“…Despite the observed antagonism between CDK4/6 inhibitors and DNA-or mitotic-damaging agents, a few studies in the last few years suggest that CDK4/6 inhibitors may actually cooperate with classical chemotherapy in some settings. Cooperative effects of CDK4/6 inhibitors with other chemotherapeutic drugs, such as cisplatin or gemcitabine have been reported in bladder, lung, ovarian, and pancreatic cancer models (Gao et al, 2017;Gelbert et al, 2014;Kumarasamy et al, 2019;Rubio et al, 2019). In ovarian cancer, CDK6 phosphorylates FOXO3 and induces ATR to protect those cells from platinum-induced cell death, supporting the use of CDK4/6 inhibitors after cisplatin to treat these tumors (Dall'Acqua et al, 2017).…”