Therapeutic evaluation of palbociclib and its compatibility with other chemotherapies for primary and recurrent nasopharyngeal carcinoma

Abstract

Background Recent genomic analyses revealed that druggable molecule targets were only detectable in approximately 6% of patients with nasopharyngeal carcinoma (NPC). However, a dependency on dysregulated CDK4/6–cyclinD1 pathway signaling is an essential event in the pathogenesis of NPC. In this study, we aimed to evaluate the therapeutic efficacy of a specific CDK4/6 inhibitor, palbociclib, and its compatibility with other chemotherapeutic drugs for the treatment of NPC by using newly established xenograft models and cell lines derived from primary, recurrent, and metastatic NPC. Methods We evaluated the efficacies of palbociclib monotherapy and concurrent treatment with palbociclib and cisplatin or suberanilohydroxamic acid (SAHA) in NPC cell lines and xenograft models. RNA sequencing was then used to profile the drug response–related pathways. Palbociclib-resistant NPC cell lines were established to determine the potential use of cisplatin as a second-line treatment after the development of palbociclib resistance. We further examined the efficacy of palbociclib treatment against cisplatin-resistant NPC cells. Results In NPC cells, palbociclib monotherapy was confirmed to induce cell cycle arrest in the G1 phase in vitro. Palbociclib monotherapy also had significant inhibitory effects in all six tested NPC tumor models in vivo, as indicated by substantial reductions in the total tumor volumes and in Ki-67 proliferation marker expression. In NPC cells, concurrent palbociclib treatment mitigated the cytotoxic effect of cisplatin in vitro. Notably, concurrent treatment with palbociclib and SAHA synergistically promoted NPC cell death both in vitro and in vivo. This combination also further inhibited tumor growth by inducing autophagy-associated cell death. NPC cell lines with induced palbociclib or cisplatin resistance remained sensitive to treatment with cisplatin or palbociclib, respectively. Conclusions Our study findings provide essential support for the use of palbociclib as an alternative therapy for NPC and increase awareness of the effective timing of palbociclib administration with other chemotherapeutic drugs. Our results provide a foundation for the design of first-in-human clinical trials of palbociclib regimens in patients with NPC.

Treatment of Recurrent Nasopharyngeal Carcinoma: A Sequential Challenge

“…Chemotherapy is one of the most classical treatment modalities for malignant tumors, and depending on the type of tumor, chemotherapy can play a “leading” or “supporting” role in the treatment process [ 96 , 97 , 98 , 99 , 100 ]. For primary NPC, radiotherapy with chemotherapy is almost the accepted treatment modality, but the “role” of chemotherapy in the treatment of recurrent NPC is still debatable [ 101 , 102 , 103 ]. Currently, several publications have reported on the treatment of recurrent NPC using different chemotherapy regimens; many oncologists believe that for patients with rT1–rT2, retreatment with radiotherapy or surgery is an option.…”

Proteomics reveals that cell density could affect the efficacy of drug treatment

“…Whether these differently expressed proteins would affect the drug effect was further tested here. We chose a specific CDK4/6 inhibitor palbocilib [ 23 ] to verify if the expression of target proteins would affect the efficiency of the corresponding target drug which are kinases that control cells to enter into the cell cycle [ 24 ]. In this study, Hep3B cells with the confluence of 30%, 50%, and 70% were treated with palbociclib of the same concentration.…”

In vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in human chordoma xenografts

“…In this current study, we explored the antitumor effect of the targeted therapy palbociclib in three PDX chordoma models in order to consider the homozygous deletion of CDKN2A/2B as a theranostic biomarker of response to palbociclib, as suggested in other cancer types (43,54,55). We observed various responses to palbociclib concerning both models (CD3, CD7) harboring a loss of CDKN2A/2B, and no tumor efficacy in the non-CDKN2A/ 2B-deleted PBRM1-mutated PDX (CD39).…”