New approaches to targeted therapy for metastatic melanoma in the presence of rare genetic changes in the tumor

Titov K.S.; Markin A.A.; Grekov D.N.; Synkova D.A.; Lisitsa T.S.; Lebedinsky I.N.

doi:https://doi.org/10.17116/onkolog20231201165

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Abstract:

Over the past 10 years, there has been a substantial melanoma treatment breakthrough that is associated with the design and use of targeted drugs. For a long period of time, BRAF/MEK and c-KIT inhibitors, as well as immunotherapy drugs have been the only targeted drugs in the treatment of melanoma. Triple-negative tumors lacking standard BRAF, NRAS, and c-KIT mutations account for up to 40% according to various sources. There are no effective treatments for this group after negative changes during immunotherapy. Therefore, in recent years, there has been an active search for new points of application of drugs to tumor DNA, its proteins and microenvironment. Investigations are underway on both driver mutations and somatic ones with oncogenic properties. However, at the moment, the Food and Drug Administration (FDA) has been approved only NTRK inhibitors to treat melanoma with rare genetic alterations. This review considers some rare molecular genetic features of tumor cells that can be used in clinical practice in the future.

Keywords:

metastatic melanoma

targeted therapy

NTRK

ALKati (alternative ALK transcription initiation)

NRAS

ERK

G9a

NF1 (neurofibromin 1)

NFkB

EVs (extracellular vesicles)

Authors:

Titov K.S.

Peoples’ Friendship University of Russia;
S.P. Botkin City Clinical Hospital

ORCID: 0000-0003-4460-9136

Markin A.A.

A.S. Loginov Moscow Resich Clinical Centr

SPIN RSCI: 6938-6460
ORCID: 0000-0002-9180-9264

Grekov D.N.

S.P. Botkin City Clinical Hospital of the Moscow Healthcare Department

Synkova D.A.

A.S. Loginov Moscow Clinical Research Center

Lisitsa T.S.

Center for Strategic Planning and Management of Medical and Biological Health Risks Federal Biomedical Agency

Lebedinsky I.N.

S.P. Botkin City Clinical Hospital Moscow City Healthcare Department

Received:

28.12.2021

Accepted:

17.02.2022

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References:

Karimkhani C, Green AC, Nijsten T, Weinstock MA, Dellavalle RP, Naghavi M, Fitzmaurice C. The global burden of melanoma: results from the Global Burden of Disease study 2015. Br J Dermatol. 2017;177(1):134-140. https://doi.org/10.1111/bjd.15510
Potekaev NN, Titov KS, Markin AA, Kashurnikov AYu. Epidemiologiya melanomy kozhi v Rossiiskoi Federatsii i v gorode Moskve za 10 let (2008—2018 gg.). Russian journal of clinical dermatology and venereology. 2020;19(6):810-816. (In Russ.). https://doi.org/10.17116/klinderma202019061810
Holderfield M, Deuker MM, McCormick F, McMahon M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer. 2014;14(7):455-467. https://doi.org/10.1038/nrc3760
Torres-Cabala CA, Wang WL, Trent J, Yang D, Chen S, Galbincea J, Kim KB, Woodman S, Davies M, Plaza JA, et al, Correlation between KIT expression and KIT mutation in melanoma: a study of 173 cases with emphasis on the acral-lentiginous/mucosal type. Mod Pathol. 2009;22(11):1446-1456. https://doi.org/10.1038/modpathol.2009.116
Steeb T, Wessely A, Petzold A, Kohl C, Erdmann M, Berking C, Heppt MV. c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma: a systematic review and one-arm meta-analysis. Eur J Cancer. 2021;157:348-357. https://doi.org/10.1016/j.ejca.2021.08.015
Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846. https://doi.org/10.1038/ncomms5846
Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, Lipson D, Otto G, Brennan K, Murali R, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun. 2014;5:3116. https://doi.org/10.1038/ncomms4116
Yeh I, Jorgenson E, Shen L, Xu M, North JP, Shain AH, Reuss D, Wu H, Robinson WA, Olshen A, et al. Targeted genomic profiling of acral melanoma. J Natl Cancer Inst. 2019;111(10):1068-1077. https://doi.org/10.1093/jnci/djz005
Lezcano C, Shoushtari AN, Ariyan C, Hollmann TJ, Busam KJ. Primary and metastatic melanoma with NTRK fusions. Am J Surg Pathol. 2018;42(8):1052-1058. https://doi.org/10.1097/PAS.0000000000001070
Marchio C, Scaltriti M, Ladanyi M, Lafrate AJ, Bibeau F, Dietel M, Hechtman JF, Troiani T, López-Rios F, Douillard JY, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019;30(9):1417-1427. https://doi.org/10.1093/annonc/mdz204
Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Turpin BD, Nathenson M, Doebele RC, Farago AF, Pappo AS, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. https://doi.org/10.1056/NEJMoa1714448
Drilon A, DuBois S, Farago AF, Geoerger B, Grilley-Olson JE, Hong DS, Sohal D, van Tilburg CM, Ziegler DS, Ku N, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. J Clin Oncol. 2019;37(15 suppl):2006. https://doi.org/10.1200/JCO.2019.37.15_suppl.2006
Drilon A, Siena S, Ou SI, Patel M, Ahn MJ, Lee J, Bauer T, Farago AF, Wheler JJ, Liu SV, et al. Safety and antitumor activity of the multitargeted Pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400-409. https://doi.org/10.1158/2159-8290.CD-16-1237
Doebele RC, Drilon A, Paz-Ares L, Siena S, Shaw AT, Farago AF, Blakely CM, Seto T, Cho BC, Tosi D Siena S, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. https://doi.org/10.1016/S1470-2045(19)30691-6
Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023. https://doi.org/10.1136/esmoopen-2015-000023
Titov KS, Markin AA, Kazakov AM, Chulkova SV. The role of a new ALK isoform in the diagnosis and targeted therapy of skin melanoma. Russian journal of biotherapy. 2021;20(4):33-41. https://doi.org/10.17650/1726-9784-2021-20-4-33-41
Wiesner T, Lee W, Obenauf AC, Ran L, Murali R, Zhang QF, Wong EW, Hu W, Scott SN, Shah RN, et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature. 2015;526(7573):453-457. https://doi.org/10.1038/nature15258
Cesi G, Philippidou D, Kozar I, Kim YJ, Bernardin F, Van Niel G, Wienecke-Baldacchino A, Felten P, Letellier E, Dengler S, et al. A new ALK isoform transported by extracellular vesicles confers drug resistance to melanoma cells. Mol Cancer. 2018;17(1):145. https://doi.org/10.1186/s12943-018-0886-x
Couts KL, Bemis J, Turner JA, Bagby SM, Murphy D, Christiansen J, Hintzsche JD, Le A, Pitts TM, Wells K, et al. ALK inhibitor response in melanomas expressing EML4-ALK fusions and alternate ALK isoforms. Mol Cancer Ther. 2018;17(1):222-231. https://doi.org/10.1158/1535-7163.MCT-17-0472
CCLE. Motivations for the Cancer Cell Line Encyclopedia (CCLE). https://portals.broadinstitute.org/ccle
Shah KK, Neff JL, Erickson LA, Jackson RA, Jenkins SM, Mansfield AS, Moser JC, Harris AL, Copland JA, Halling KC, Flotte TJ. Correlation of novel ALKATI with ALK immunohistochemistry and clinical outcomes in metastatic melanoma. Histopathology. 2020;77(4):601-610. https://doi.org/10.1111/his.14191
Holla VR, Elamin YY, Bailey AM, Johnson AM, Litzenburger BC, Khotskaya YB, Sanchez NS, Zeng J, Shufean MA, Shaw KR, et al. ALK: a tyrosine kinase target for cancer therapy. Cold Spring Harb Mol Case Stud. 2017;3(1):a001115. https://doi.org/10.1101/mcs.a001115
Zito Marino F, Liguori G, Aquino G, La Mantia E, Bosari S, Ferrero S, Rosso L, Gaudioso G, De Rosa N, Scrima M, et al. Intratumor heterogeneity of ALK-rearrangements and homogeneity of EGFR-mutations in mixed lung adenocarcinoma. PLoS One. 2015;10(9):e0139264. https://doi.org/10.1371/journal.pone.0139264
Inam H, Sokirniy I, Rao Y, Shah A, Naeemikia F, O’Brien E, Dong C, McCandlish DM, Pritchard JR. Genomic and experimental evidence that ALKATI does not predict single agent sensitivity to ALK inhibitors. iScience. 2021;24(11):103343. https://doi.org/10.1016/j.isci.2021.103343
Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol. 2007;127(1):179-182. https://doi.org/10.1038/sj.jid.5700490
Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(4):435-445. https://doi.org/10.1016/S1470-2045(17)30180-8
Lebbe C, Dutriaux C, Lesimple T, Kruit W. Pimasertib (PIM) versus dacarbazine (DTIC) in patients (pts) with cutaneous NRAS melanoma: a controlled, openlabel phase II trial with crossover. Ann Oncol. 2016;27(suppl 6):1136.
Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, Schuman SS, Shea JE, Seipp MT, Yap JT, et al. Protective autophagy elicited by RAF!MEK!ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019;25(4):620-627. https://doi.org/10.1038/s41591-019-0367-9
U.S. National Library of Medicine. ClinicalTrials.gov. Study of CDX-3379, a human monoclonal antibody targeting ERBB3, in combination with the MEK inhibitor, Trametinib, in patients with advanced stage NRAS mutant and BRAF/NRAS Wildtype (WT) melanoma. https://clinicaltrials.gov/ct2/show/NCT03580382
Clinical trial. Phase I study of HL-085 in patients with advanced solid tumor tumors. https://www.wikidata.org/wiki/Q104675844
U.S. National Library of Medicine. ClinicalTrials.gov. MEK and autophagy inhibition in metastatic/locally advanced, unresectable neuroblastoma RAS (NRAS) Melanoma (CHLOROTRAMMEL). https://clinicaltrials.gov/ct2/show/NCT03979651
Merchant M, Moffat J, Schaefer G, Chan J, Wang X, Orr C, Cheng J, Cheng J, Hunsaker T, Shao L, et al. Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors. PLoS One. 2017;12(10):e0185862. https://doi.org/10.1371/journal.pone.0185862
Moschos SJ, Sullivan RJ, Hwu WJ, Ramanathan RK, Adjei A, Fong PC, Shapira-Frommer R, Tawbi HA, Rubino J, Rush TS 3rd, et al. Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight. 2018;3(4):e92352. https://doi.org/10.1172/jci.insight.92352
Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, Patel MR, Shapiro GI, Mier JW, Tolcher AW, et al. First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study. Cancer Discov. 2018;8(2):184-195. https://doi.org/10.1158/2159-8290.CD-17-1119
U.S. National Library of Medicine. ClinicalTrials.gov. A study of LY3214996 administered alone or in combination with other agents in participants with advanced/metastatic cancer. https://clinicaltrials.gov/show/NCT02857270
U.S. National Library of Medicine. ClinicalTrials.gov. A study of ASN007 in patients with advanced solid tumors. https://clinicaltrials.gov/ct2/show/NCT03415126
Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129(4):823-837. https://doi.org/10.1016/j.cell.2007.05.009
Thomas LR, Miyashita H, Cobb RM, Pierce S, Tachibana M, Hobeika E, Reth M, Shinkai Y, Oltz EM. Functional analysis of histone methyltransferase G9a in B and T lymphocytes. J Immunol. 2008;181(1): 485-493. https://doi.org/10.4049/jimmunol.181.1.485
Pereira RM, Martinez GJ, Engel I, Cruz-Guilloty F, Barboza BA, Tsagaratou A, Lio CWJ, Berg LJ, Lee Y, Kronenberg M, et al. Jarid2 is induced by TCR signalling and controls iNKT cell maturation. Nat Commun. 2014;5:4540. https://doi.org/10.1038/ncomms5540
Kato S, Weng QY, Insco ML, Chen KY, Muralidhar S, Pozniak J, Diaz JMS, Drier Y, Nguyen N, Lo JA, et al. Gain-of-function genetic alterations of G9a drive oncogenesis. Cancer Discov. 2020;10(7):980-997. https://doi.org/10.1158/2159-8290.CD-19-0532
Serre C, Busuttil V, Botto JM. Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation. Int J Cosmet Sci. 2018;40(4):328-347. https://doi.org/10.1111/ics.12466
Dang NN, Jiao J, Meng X, An Y, Han C, Huang S. Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway. Aging (Albany NY). 2020;12(3):2393-2407. https://doi.org/10.18632/aging.102750
Porcelli L, Mazzotta A, Garofoli M, Di Fonte R, Guida G, Guida M, Tommasi S, Azzariti A. Active notch protects MAPK activated melanoma cell lines from MEK inhibitor cobimetinib. Biomed Pharmacother. 2021;133:111006. https://doi.org/10.1016/j.biopha.2020.111006
Ma W, Han C, Zhang J, Song K, Chen W, Kwon H, Wu T. The histone methyltransferase G9a promotes cholangiocarcinogenesis through regulation of the hippo pathway kinase LATS2 and YAP signaling pathway. Hepatology. 2020;72(4):1283-1297. https://doi.org/10.1002/hep.31141
Shao H, Moller M, Cai L, Prokupets R, Yang C, Costa C, Yu K, Le N, Liu ZJ. Converting melanoma-associated fibroblasts into a tumor-suppressive phenotype by increasing intracellular Notch1 pathway activity. PLoS ONE. 2021;16(3):e0248260. https://doi.org/10.1371/journal.pone.0248260
Du Y, Shao H, Moller M, Prokupets R, Tse YT, Liu ZJ. Intracellular Notch1 signaling in cancer-associated fibroblasts dictates the plasticity and stemness of melanoma stem/initiating cells. Stem Cells. 2019;37(7):865-75. https://doi.org/10.1002/stem.3013
Maeda K, Hamada JI, Takahashi Y, Tada M, Yamamoto Y, Sugihara T, Moriuchi T. Altered expressions of HOX genes in human cutaneous malignant melanoma. Int J Cancer. 2005;114(3):436-441. https://doi.org/10.1002/ijc.20706
Li Q, Dong C, Cui J, Wang Y, Hong X. Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme. J Exp Clin Cancer Res. 2018;37(1):265. https://doi.org/10.1186/s13046-018-0941-x
Ke XX, Zhang R, Zhong X, Zhang L, Cui H. Deficiency of G9a inhibits cell proliferation and activates autophagy via transcriptionally regulating c-Myc expression in glioblastoma. Front Cell Dev Biol. 2020;8:593964. https://doi.org/10.3389/fcell.2020.593964
Yin C, Ke X, Zhang R, Hou J, Dong Z, Wang F, Zhang K, Zhong X, Yang L, Cui H. G9a promotes cell proliferation and suppresses autophagy in gastric cancer by directly activating mTOR. FASEB J. 2019;33(12):14036-14050. https://doi.org/10.1096/fj.201900233RR
Kelly GM, Al-Ejeh F, McCuaig R, Casciello F, Ahmad Kamal NA, Ferguson B, Pritchard AL, Ali S, Silva IP, Wilmott JS, et al. G9a inhibition enhances checkpoint inhibitor blockade response in melanoma. Clin Cancer Res. 2021;27(9):2624-2635. https://doi.org/10.1158/1078-0432.CCR-20-3463
Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, Fischer M, Chaudhari A, Ji M, Kapoun AM, et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA. 2012;109(29):11717-11722. https://doi.org/10.1073/pnas.1120068109
Teixido C, Castillo P, Martinez-Vila C, Arance A, Alos L. Molecular markers and targets in melanoma. Cells. 2021;10(9):2320. https://doi.org/10.3390/cells10092320
Nissan MH, Pratilas CA, Jones AM, Ramirez R, Won H, Liu C, Tiwari S, Kong L, Hanrahan AJ, Yao Z, et al. Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Res. 2014;74(8):2340-2350. https://doi.org/10.1158/0008-5472.CAN-13-2625
Dey A, Wong E, Kua N, Teo HL, Tergaonkar V, Lane D. Hexamethylene bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF-κappaB activity: implications for cancer therapy. Cell Cycle. 2008;7(23):3759-3767. https://doi.org/10.4161/cc.7.23.7213
Takács A, Lajkó E, Láng O, Istenes I, Kőhidai L. Alpha-lipoic acid alters the antitumor effect of bortezomib in melanoma cells in vitro. Sci Rep. 2020;10(1):14287. https://doi.org/10.1038/s41598-020-71138-z
Croghan GA, Suman VJ, Maples WJ, Albertini M, Linette G, Flaherty L, Eckardt J, Ma C, Markovic SN, Erlichman C. A study of paclitaxel, carboplatin, and bortezomib in the treatment of metastatic malignant melanoma: a phase 2 consortium study. Cancer. 2010;116(14):3463-3468. https://doi.org/10.1002/cncr.25191
Ukrainskaya VM, Rubtsov JuP, Knorre VD, Maschan MA, Gabibov AG, Stepanov AV. Vezikuly, sekretiruemye opukholevymi kletkami, i ikh rol’ v regulyatsii protivoopukholevogo immuniteta. Acta Naturae. 2019;11(4):33-41. (In Russ.). https://doi.org/10.32607/20758251-2019-11-4-33-41
Mulcahy LA, Pink RC, Carter DR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;3. https://doi.org/10.3402/jev.v3.24641
Homicsko K, Russell K, Voss A, Michielin O. Triple wild type melanoma profiling in the Caris Molecular Intelligence registry. J Clin Oncol. 2015;33(15 suppl):9054. https://doi.org/10.1200/JCO.2015.33.15_SUPPL.9054