Palbociclib in advanced acral melanoma with genetic aberrations in the cyclin-dependent kinase 4 pathway

Mao, Lili; Dai, Jie; Cao, Yabing; Bai, Xue; Sheng, Xinan; Chen, Zhihong; Cui, Chuanliang; Kong, Yan; Zhang, Yanxiang; Wu, Lin; Wang, Xuan; Tang, Bixia; Lian, Bin; Yan, Xieqiao; Li, Siming; Zhou, Li; Wei, Xiaoting; Li, Caili; Qi, Zhonghui; Si, Lu; Guo, Jun

doi:10.1016/j.ejca.2021.02.021

Cited by 28 publications

(23 citation statements)

References 31 publications

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“…CDK4 gene amplification has been found in numerous types of cancer including breast cancer ( 30 ), sarcoma ( 31 ), cervical cancer ( 32 ), and melanoma ( 33 ). The effect of CDK4 amplification on CDK4/6i sensitivity remains controversial; although it enhanced sensitivity in liposarcoma ( 34 ), it caused resistance in glioblastoma ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Combining a CDK4/6 Inhibitor With Pemetrexed Inhibits Cell Proliferation and Metastasis in Human Lung Adenocarcinoma

et al. 2022

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BackgroundRecent clinical trials of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in human lung adenocarcinoma (LUAD) have not achieved satisfactory results. The disappointing results of single-drug treatments have prompted studies about synergistic therapies of CDK4/6i with other drugs. We aimed to test the anti-tumor effect of ribociclib (a CDK4/6i) combined with pemetrexed on LUAD and the potential mechanisms.MethodsCell lines were exposed to ribociclib and pemetrexed at different doses. Antitumor effects were measured using growth inhibition. Cell cycle distribution and apoptosis were evaluated using flow cytometry. Cell migration and invasion were measured using wound healing and transwell invasion assays, respectively. The expression levels of proteins were analyzed using western blotting. Mice xenograft models were used for validation in vivo.ResultsSynergism was associated with a combination of cell cycle effects from both agents. Cell cycle analysis revealed that pemetrexed blocked cells in the S phase, whereas ribociclib arrested cells in the G1 phase. Concomitant treatment with pemetrexed and ribociclib resulted in a significantly stronger antitumor ability than treatment alone. We also found that ribociclib strongly enhanced the pro-apoptotic activity of pemetrexed via the caspase/bcl-2 signaling pathway. In addition, we report for the first time that combination treatment with ribociclib and pemetrexed significantly inhibits the migration and invasion of LUAD cells.ConclusionsCombining ribociclib and pemetrexed showed a powerful ability to inhibit cancer proliferation, invasion, and metastasis, and it holds potential as a novel effective combinative therapy for patients with LUAD.

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Section: Discussionmentioning

confidence: 99%

Combining a CDK4/6 Inhibitor With Pemetrexed Inhibits Cell Proliferation and Metastasis in Human Lung Adenocarcinoma

et al. 2022

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“…Of interest, the patient with the partial response had CCND1 amplification. In regards to Palbociclib, a phase 1 trial in China evaluated its efficacy in patients with acral lentiginous melanomas with CDKN2A pathway alterations [ 141 ]. Among the 15 patients enrolled in this trial, there were three documented responses (an ORR of 20%) with one achieving a PR with palbociclib monotherapy.…”

Section: Targeting Tumor Suppressor Gene Alterationsmentioning

confidence: 99%

Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches

Khaddour

Maahs

Avila-Rodriguez

et al. 2021

Cancers

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Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date, BRAF and MEK inhibitors remain the only approved targeted therapy with a high level of evidence in BRAFV600E/K mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, advocates for further research to unveil effective therapeutics. In this review, we will discuss potential druggable mutations and the ongoing research of novel individualized treatment approaches targeting non-BRAF mutations in melanomas.

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“…The dysregulation of cell cycle progression, caused by CDK4 amplification and/or CCND1 amplification and/or p16 ( CDKN2A ) loss, is a key genetic feature in mucosal melanoma [ 11 ]. Targeting CDK4/6 is a promising therapeutic strategy that is supported by a strong preclinical rationale and some case reports of response to the CDK4/6 inhibitor, palbociclib [ 11 , 36 , 37 ]. To date, the use of CDK4/6 inhibitors in patients with mucosal melanoma harboring amplification of CDK4 is under evaluation in clinical trials ( Table 2 ).…”

Section: Therapeutic Approachmentioning

confidence: 99%

“…VEGF expression was associated with poor survival outcomes among patients with primary mucosal melanoma of the oral cavity, suggesting it could be a potential therapeutic target. Unfortunately, preliminary data of antiangiogenic drugs, either alone or combined with cytotoxic chemotherapy, have yielded only limited antitumor activity and therapeutic results [ 37 , 58 ]. Inhibition of the VEGF signaling pathway also exerts immune-mediated effects in the tumor microenvironment.…”

Section: Ongoing Clinical Trials and Future Perspectivesmentioning

confidence: 99%

Molecular Profiling and Novel Therapeutic Strategies for Mucosal Melanoma: A Comprehensive Review

Indini

Roila

Grossi

et al. 2021

IJMS

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Mucosal melanoma is a rare and aggressive subtype of melanoma. Unlike its cutaneous counterpart, mucosal melanoma has only gained limited benefit from novel treatment approaches due to the lack of actionable driver mutations and poor response to immunotherapy. Over the last years, whole-genome and exome sequencing techniques have led to increased knowledge on the molecular landscape of mucosal melanoma. Molecular studies have underlined noteworthy findings with potential therapeutic implications, including the presence of KIT mutations, which are potential targets of tyrosine kinase inhibitors currently in use in the clinic (imatinib), but also SF3B1 mutation, CDK4 amplifications, and CDKN2A gene deletions, which are presently under investigation in clinical trials. Recent results from a pooled analysis of patients with mucosal melanoma treated with immunotherapy have suggested that the combination of immune checkpoint inhibitors might improve survival outcomes in this subset of patients, as compared with single-agent immunotherapy. However, these results are not confirmed across different studies, and combo-immunotherapy correlates with a higher rate of adverse events. In this review, we describe the clinical, biological, and genetic features of mucosal melanoma. We also provide an update on the results of approved systemic treatment in this setting and overview the therapeutic strategies currently under investigation in clinical trials.

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Palbociclib in advanced acral melanoma with genetic aberrations in the cyclin-dependent kinase 4 pathway

Cited by 28 publications

References 31 publications

Combining a CDK4/6 Inhibitor With Pemetrexed Inhibits Cell Proliferation and Metastasis in Human Lung Adenocarcinoma

Combining a CDK4/6 Inhibitor With Pemetrexed Inhibits Cell Proliferation and Metastasis in Human Lung Adenocarcinoma

Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches

Molecular Profiling and Novel Therapeutic Strategies for Mucosal Melanoma: A Comprehensive Review

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