Peyton Harris

 Background: Melanoma, which is the 19th most common cancer diagnosed throughout the world, is a malignant tumor arising from melanocytes.^{1, 4} While melanoma makes up only 3-5% of skin cancers, 65% of skin cancer related deaths are a result of melanoma.^{1, 4} Treatment options include surgical excision as the first-line treatment in most cases, with utilization of immunotherapy (e.g. PD1 antibodies) chemotherapy, radiation, targeted therapy (e.g. BRAF and MEK inhibitors), or a combination of multiple therapies in more advanced cases.^2,3,5 While there is an initial favorable response to BRAF inhibitors (BRAFi) or BRAFi/MEK inhibitor (MEKi) combination, melanoma tumors with a BRAF^V600 mutation (valine to glutamic acid substituation at codon 600) almost all cell lines develop an acquired resistance.⁶ Acquired BRAFi resistance has been linked to several mutations including those impacting CDKN2A, indicating a potential therapeutic target in overcoming BRAFi resistance.^6,7

Objective: This literature review explored potential mechanisms by which BRAFi resistant melanoma can be overcome.

Search Methods: An online PubMed search using the keywords: “melanoma”, “cdk4/6”, “braf resistance”, “treatment” from from 2017 to 2023 was conducted.

Results: Mutations of CDKN2A, lead to aberrant cell-cycle progression and tumorigenesis resulting from increased cyclin D1-CDK4/6 activity.⁸ Studies show the therapeutic combination of a CDK4/6 inhibitor (CDK4/6i) plus a MEKi decreases tumor proliferation, increases cell cycle arrest and inhibition of downstream signaling for the MAPK pathways, and decreased growth of melanoma cells.⁸ Additionally, loss of CDKN2A was associated with a greater sensitivity to the CDK4/6i, palbociclib, indicating CDKN2A may be a marker of treatment response⁸ Furthermore, CDK4/6i were effective at halting cell proliferation and preventing BRAFi resistance when used in treatment-naive cells, suggesting that treatment outcomes may be improved by initiating a combination therapy from initial melanoma diagnosis.⁹ p53, a tumor supressor involved in DNA repair, is frequently mutated in melanoma, leading to uncontrolled cell cycle and tumor progression. A study investigating the role of p53 in the response to palbociclib found decreased cell proliferation in cell lines with greater p53 expression, indicating that the activation of p53 impacts response to palbociclib.¹⁰ CHEK2, a protein kinase involved in cell cycle regulation and arrest, as well as stabilization of p53, could be a potential marker for sensitivity of melanoma tumors to palbociclib treatment, as patients expressing greater levels of CHEK2 showed greater response to palbociclib, as measured by decreased cell proliferation.¹¹ This was further supported by increased cell proliferation in cell lines with decreased CHEK2 expression and decreased cell proliferation when palbociclib was combined with the CHEK2 activator, 3,3’-diindolylmethane (DIM).¹¹

Conclusion: Studies show that CHEK2 stabilizes p53, p53 activation improves response to CDK4/6 inhibitors, and CDK4/6 inhibitors overcome BRAF inhibitor resistance when used early in the treatment course.^6,8,9,10,11 Utilization of CDK4/6 inhibition in combination with a CHEK2 activator, such as DIM, should be considered for melanoma showing inadequate response or BRAF/MEKi resistance.

 Works Cited:

1. Naik PP. Cutaneous Malignant Melanoma: A Review of Early Diagnosis and Management. World J Oncol. 2021;12(1):7-19. doi:10.14740/wjon1349
2. Davey MG, Miller N, McInerney NM. A Review of Epidemiology and Cancer Biology of Malignant Melanoma. Cureus. 2021; 13(5):15087. Published 2021 May 18. doi:10.7759/cureus.15087
3. Hartman RI, Lin JY. Cutaneous Melanoma–A Review in Detection, Staging, and Management. Hematol Oncol Clin N Am. 2019;33(1):25-38. doi:10.1016/j.hoc.2018.09.005
4. Lopes K, Rodrigues CMP, Gaspar MM, Pinto Reis C. Melanoma Management: From Epidemiology to Treatment and Latest Advances. Cancers (Basel). 2022; 14(19):4652. Published 2022 Sep 24. doi:10.3390/cancers14194652
5. Guo L, Qi J, Wang H, Jiang X, Liu Y. Getting under the skin: The role of CDK4/6 in melanomas. Eur J Med Chem. 2020;204:11253. doi:10.1016/j.ejmech.2020.112531
6. Irvine M, Stewart A, Pedersen B, Boyd S, Kefford R, Rizos H. Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma. Oncogenesis. 2018;7(9):72. Published 2018 Sep 20. doi:10.1038/s41389-018-0081-3
7. Garutti M, Targato G, Buriolla S, et al. CDK4/6 Inhibitors in Melanoma: A Comprehensive Review. Cells. 2021;10(6):1334. Published 2021 May 28. doi:10.3390/cells10061334
8. Nassar KW, Hintzche JD, Bagby SM, et al. Targeting CDK4/6 Represents a Therapeutic Vulnerability in Acquired BRAF/MEK Inhibitor-Resistant Melanoma. Mol Cancer Ther. 2021; 20(10):2049-2060. doi:10.1158/1535-7163.MCT-20-1126
9. Martin CA, Cullinane C, Kirby L, et al. Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance. Int J Cancer. 2018;142(10):2139-2152. doi:10.1002/ijc.31220
10.  AbuHammad S, Cullinane C, Martin C, et al. Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma [published correction appears in Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9644-9645]. Proc Natl Acad Sci U S A. 2019;116(36):17990-18000. doi:10.1073/pnas.1901323116
11. Louveau B, Resche-Rigon M, Lesimple T, et al. Phase I-II Open-Label Multicenter Study of Palbociclib + Vemurafenib in BRAFV600MUT Metastatic Melanoma Patients: Uncovering CHEK2 as a Major Response Mechanism. Clin Cancer Res. 2021;27(14):3876-3883. doi:10.1158/1078-0432.CCR-20-4050