The action of Palbociclib on the Cell Cycle of Head and Neck Squamous Cell Carcinoma: A Systematic Review

Tumor cells have various molecular characteristics, which, due to their abundance, end up hindering the effectiveness of traditional cancer treatments, whose approach, in most cases, is tissue-based rather than molecular. From the moment it became possible to know the molecular alterations of the cells, and to carry out genetic sequencing of the tumor, more specific treatments were created, the so-called tumor-agnostic treatments, aimed at this cellular information, and not dependent on the type of tissue the cell is part of. Thus, it is necessary to monitor the progression of the tumors and its molecular alterations throughout treatment, since it ends up being highly selective to certain specific molecular alterations, so the drugs used in this type of treatment are active against different subtypes of oncogene-dependent cancers.1 2 3 4 5 6

In head and neck squamous cell carcinoma, there is usually activation of the epidermal growth factor receptor (EGFR). In human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCCs) cases, which show a better response to cyclin inhibitors, the development pattern is usually based on inactivation of p16INK4A and overexpression of cyclin D1, resulting in hyperactivation of cyclin-dependent kinase 4 and 6 (CDK4/6). This is because the loss of p16 functionality allows CDK4/6 to complex with cyclin D and then phosphorylate and inactivate Rb, releasing E2F and progressing to the G1 phase, after the first checkpoint, and advancing to the S phase of the cell cycle. Thus, loss of checkpoint regulation leads to uncontrolled cell proliferation, allowing cancer cells to multiply exacerbatedly.7 8 9 10 11 12 13

Increased expression of cyclin or CDKs or decreased levels of endogenous CDK inhibitors, such as INK4 or CIP/KIP, is found in many cancers, while mutations in genes encoding CDKs that cause cancer are rare. In this way, CDKs end up becoming targets for cancer therapies.14 15

Dual CDK4/6 inhibitors have shown significant efficacy in preclinical and clinical cancer therapies, especially in breast cancer, as single agents or combined with hormonal treatments, chemotherapy, radiotherapy, or immunotherapy. It is, therefore, considered necessary to review the action of these drugs on the cell cycle of cancer cells, to provide us with therapeutic possibilities14 15

Although CDK4/6 inhibition results in a decrease in cell multiplication and leads to an interruption of the cell cycle, it is likely that cell senescence or senescence-like activity is a crucial mechanism associated with the clinical efficacy of this medication. Cellular senescence is the phenomenon in which a cell experiences a permanent and irreversible interruption of its growth in response to cellular stresses, such as unrepaired DNA damage, which renders it resistant to mitogenic stimulation and oncogenic challenges.8

An example of a CDK4/6 inhibitor is palbociclib, which is currently approved by the Food and Drug Administration (FDA) only for the treatment of breast cancer, but has been the subject of several clinical trials in other types of cancer, including head and neck squamous cell carcinoma.14 16 Palbociclib is a highly effective and selective oral inhibitor of the cyclin-dependent kinase CDK4/6, with robust preclinical data supporting its effectiveness in tumors that show retinoblastoma protein expression.17

This inhibitor acts on cells in such a way as to decrease phosphorylated Rb, and consequently restore the function of p16, bringing back the effectiveness of the first G1 checkpoint, causing cell replication to occur only in healthy cells, and preventing the exacerbated multiplication of mutant cancer cells. In other words, this drug inhibits the progression from G1 to S in defective cells, leaving them in what is known as a senescent state, which allows these cells to respond more effectively to conventional treatments.8 12 13

The present study aims to understand how the genetic composition of head and neck squamous cell carcinoma cells is affected by CDK4/6 cyclin inhibitors, especially palbociclib, to understand, based on a comparison between the cellular alterations that trigger this cancer, how the aforementioned drug, currently used in HER-negative breast cancers, has been responding in the therapy of cancers of other systems.

The current systematic review, conducted without a meta-analysis, is registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42024539528.

The study by Michel et al. (2016)⁷ shows that of the 9 patients included in the study, 6 were resistant to Cetuximab, and 4 were resistant to platinum, with 1 of the 9 being resistant to both medications. It is worth noting that most of the patients had a history of smoking. As for the response to the combination treatment of palbociclib and cetuximab, the best tumor response was seen in two patients, and there was no description of the patients who had a partial response. Stable disease was seen in 6 patients and disease progression was observed in only 1 patient. In the present study, the average duration of response was 112 days.

The study by Adkins et al. (2019)⁹ assessed 62 patients diagnosed with HNSCC, most commonly in the larynx and oral cavity. They were divided into 2 groups, the 1st with 30 patients with HPV-negative HNSCC without previous use of cetuximab, but resistant to platinum, 2 of whom died early. Of the 28 evaluated in this group, 3 showed the best response and 8 showed a partial response, 14 maintained stable disease, and 3 progressed. The median duration of response for this group was 4 months.

In the 2nd group, 32 patients were selected who were resistant to the use of cetuximab in monotherapy; of these, 5 were not evaluable. Of the remaining 27, 1 showed a better response and 4 a partial response, 13 showed disease stability, and the other 9 progressed. The median duration of response for this group was 6 months. The groups were followed up for an average of 5.4 months, making it possible to extract the results described. Table 1.

The present systematic review shows that the use of a CDK4/6 cyclin inhibitor, palbociclib, is capable of bringing a cancer cell to a state of senescence, regulating cell proliferation, which is out of control, and restoring the function of the G1 to S checkpoint of the cell cycle, which was lost during the mutation that turned the cell into a cancer.8

The drug in question is part of the treatment protocol for HR+ breast cancer only and is not approved by the FDA for any other type of tumor. However, clinical trials show relative evidence of this drug in other cancers, including HPV-negative HNSCC, which was the focus of the current study.

Looking at other systematic reviews, the similarities between the most common defects found in the cell cycle of head and neck squamous cell carcinoma and HR+ breast cancer are clear. Van Caloen et al. (2019)10 shows that HNSCC is driven by inactivation of the p16-INK4a and TP53 proteins, as well as amplification of the CCND1 protooncogenes and inactivation of the CDKN2A tumor suppressor gene. Similarly, Clark et al. (2016)17 found that palbociclib showed greater antiproliferative effects in HR+ breast cancer cells through the loss of p16 or the increase in CCND1, and, thus, after completing the 3 phases of the Palbociclib: Ongoing Trials in the Management of Breast Cancer (PALOMA) study, was included as a therapeutic option for this type of tumor, in association with antiestrogens, including letrozole and fulvestrant.

This similarity gives rise to the guiding question of this systematic review, which asks how palbociclib, approved only for HR+ breast cancer, can also be effective in head and neck squamous cell carcinoma. There are no studies in the literature that clearly demonstrate this mechanism, but some describe results that allow us to think about a future inclusion of palbociclib, in association with an EGF2 inhibitor, cetuximab, to prolong the prognosis of HNSCC.

Billard-Sandu et al. (2020)12 point out that HPV-negative HNSCC generally has a poor prognosis, which encourages the search for new treatment strategies. Given that EGFR inhibitors show a satisfactory response in the treatment of this cancer, the pattern of genetic alterations found in the pathology in question has the potential to cause a decrease in the effectiveness of EGFR inhibitors, corroborating with the lower survival of patients.

For this reason, new medications are being studied to improve the prognosis of HNSCC, including palbociclib, which allows for slower disease progression, possibly explained by its action at a different stage of the cell cycle of these cells, when compared with cetuximab in monotherapy. The CDK4/6 cyclin inhibitor decreases phosphorylated Rb and, consequently, restores the function of p16, bringing back the effectiveness of the first G1 checkpoint, causing cell replication to occur only in healthy cells, and preventing the exacerbated multiplication of mutant cancer cells. In other words, this drug inhibits the progression from G1 to S in defective cells, leaving them in what is known as a senescent state, which allows these cells to respond more effectively to conventional treatments, including cetuximab.8 12

To confirm the hypothesis discussed in this paper, clinical trials were analyzed that studied the clinical response of several patients with HPV-negative HNSCC, using palbociclib associated with cetuximab. Analyzing the results of Adkins et al. (2019),9 we see that of the 62 patients studied, only 12 showed disease progression, the others showed a complete or partial response, or kept the disease stable, bringing a favorable result, in relation to disease progression, when compared with the isolated use of drugs or even in relation to patients who underwent chemotherapy with platinum derivatives.

In this same study, it was shown that the duration of response, although satisfactory, was shorter with the use of the combination of palbociclib and cetuximab than with PD-1 inhibitors, but progression-free survival was higher in patients who used the combination compared with those who used monotherapy.

Looking at the results of the clinical trial by Michel et al. (2016),7 of the 9 patients evaluated, only one showed disease progression, with the others showing a complete response or stabilization of the disease. Thus, it is argued that both the rate of disease control and the duration of response were superior in relation to the same parameters in monotherapy.

Finally, this systematic review presents important aspects, showing a clear correlation between the genetic alterations found in HNSCC and HR+ breast cancer, allowing the same CDK4/6 cyclin inhibitor to be used in both pathologies in association with the conventional medications already known for each of them. Therefore, the effectiveness of palbociclib in HNSCC is not clearly described, due to the lack of studies in the area, but the few that were found show that there is a possibility of including this medication in the therapeutic regimen for this cancer, requiring further clinical studies to strengthen this hypothesis.

The present systematic review indicates that the CDK4/6 inhibitor palbociclib has promising potential to induce senescence in tumor cells and modulate cell proliferation and is currently approved only for the treatment of HR+ and HER2- breast cancer. The preliminary studies discussed in this review suggest a possible applicability in other types of cancer, such as HPV-negative HNSCC, given the similarity in the mechanisms of cell cycle deregulation.

The clinical studies analyzed report that the combination of palbociclib with cetuximab demonstrated relevant antitumor activity, especially in cases resistant to platinum and to cetuximab itself, with superior results to monotherapy in terms of progression-free survival. However, the exact mechanisms by which palbociclib acts in this context are not yet fully elucidated. Furthermore, the scarcity of studies on this subject in the literature limits the strength of the conclusions, reinforcing the need for further clinical and preclinical investigations to validate the role of palbociclib in this therapeutic scenario.