Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes

Indira Pla; Botond L Szabolcs; Petra Nikolett Péter; Zsuzsanna Ujfaludi; Yonghyo Kim; Peter Horvatovich; Aniel Sanchez; Krzysztof Pawlowski; Elisabet Wieslander; Magdalena Kuras; Jimmy Rodriguez Murillo; Jéssica Guedes; Dorottya M P Pál; Anna A Ascsillán; Lazaro Hiram Betancourt; István Balázs Németh; Jeovanis Gil; Natália Pinto de Almeida; Beáta Szeitz; Leticia Szadai; Viktória Doma; Nicole Woldmar; Áron Bartha; Zoltan Pahi; Tibor Pankotai; Balázs Győrffy; A Marcell Szasz; Gilberto Domont; Fábio Nogueira; Ho Jeong Kwon; Roger Appelqvist; Sarolta Kárpáti; David Fenyö; Johan Malm; György Marko-Varga; Lajos V Kemény

doi:10.1111/ijd.17586

Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes

Indira Pla, Botond L Szabolcs, Petra Nikolett Péter, Zsuzsanna Ujfaludi, Yonghyo Kim, Peter Horvatovich, Aniel Sanchez, Krzysztof Pawlowski, Elisabet Wieslander, Magdalena Kuras, Jimmy Rodriguez Murillo, Jéssica Guedes, Dorottya M P Pál, Anna A Ascsillán, Lazaro Hiram Betancourt, István Balázs Németh, Jeovanis Gil, Natália Pinto de Almeida, Beáta Szeitz, Leticia SzadaiViktória Doma, Nicole Woldmar, Áron Bartha, Zoltan Pahi, Tibor Pankotai, Balázs Győrffy, A Marcell Szasz, Gilberto Domont, Fábio Nogueira, Ho Jeong Kwon, Roger Appelqvist, Sarolta Kárpáti, David Fenyö, Johan Malm, György Marko-Varga, Lajos V Kemény^*

^*Corresponding author for this work

Analytical Biochemistry

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem.

OBJECTIVE: Here, we mine large-scale MM proteogenomic data to identify druggable targets and forecast treatment efficacy and resistance.

METHODS: Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC, and AKT1, across five distinct MM subtypes. These proteins are potential drug targets applicable to one or multiple MM subtypes. Additionally, by integrating proteogenomic profiles obtained from MM subtypes with MM cell line dependency and drug sensitivity data, we identified a total of 162 potentially targetable genes. Lastly, we identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype.

RESULTS: Employing these unbiased approaches, we have uncovered compounds targeting ferroptosis demonstrating a striking 30× fold difference in sensitivity among different subtypes.

CONCLUSIONS: Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy.

Original language	English
Pages (from-to)	870-881
Number of pages	12
Journal	International journal of dermatology
Volume	64
Issue number	5
Early online date	25-Dec-2024
DOIs	https://doi.org/10.1111/ijd.17586
Publication status	Published - May-2025

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Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma SubtypesFinal publisher's version, 2.38 MBLicence: CC BY-NC

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Pla, I., Szabolcs, B. L., Péter, P. N., Ujfaludi, Z., Kim, Y., Horvatovich, P., Sanchez, A., Pawlowski, K., Wieslander, E., Kuras, M., Murillo, J. R., Guedes, J., Pál, D. M. P., Ascsillán, A. A., Betancourt, L. H., Németh, I. B., Gil, J., de Almeida, N. P., Szeitz, B., ... Kemény, L. V. (2025). Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes. International journal of dermatology, 64(5), 870-881. https://doi.org/10.1111/ijd.17586

@article{96690e152408482ea553fa990f6b9608,

title = "Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes",

abstract = "BACKGROUND: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem.OBJECTIVE: Here, we mine large-scale MM proteogenomic data to identify druggable targets and forecast treatment efficacy and resistance.METHODS: Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC, and AKT1, across five distinct MM subtypes. These proteins are potential drug targets applicable to one or multiple MM subtypes. Additionally, by integrating proteogenomic profiles obtained from MM subtypes with MM cell line dependency and drug sensitivity data, we identified a total of 162 potentially targetable genes. Lastly, we identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype.RESULTS: Employing these unbiased approaches, we have uncovered compounds targeting ferroptosis demonstrating a striking 30× fold difference in sensitivity among different subtypes.CONCLUSIONS: Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy.",

author = "Indira Pla and Szabolcs, {Botond L} and P{\'e}ter, {Petra Nikolett} and Zsuzsanna Ujfaludi and Yonghyo Kim and Peter Horvatovich and Aniel Sanchez and Krzysztof Pawlowski and Elisabet Wieslander and Magdalena Kuras and Murillo, {Jimmy Rodriguez} and J{\'e}ssica Guedes and P{\'a}l, {Dorottya M P} and Ascsill{\'a}n, {Anna A} and Betancourt, {Lazaro Hiram} and N{\'e}meth, {Istv{\'a}n Bal{\'a}zs} and Jeovanis Gil and {de Almeida}, {Nat{\'a}lia Pinto} and Be{\'a}ta Szeitz and Leticia Szadai and Vikt{\'o}ria Doma and Nicole Woldmar and {\'A}ron Bartha and Zoltan Pahi and Tibor Pankotai and Bal{\'a}zs Gy{\H o}rffy and Szasz, {A Marcell} and Gilberto Domont and F{\'a}bio Nogueira and Kwon, {Ho Jeong} and Roger Appelqvist and Sarolta K{\'a}rp{\'a}ti and David Feny{\"o} and Johan Malm and Gy{\"o}rgy Marko-Varga and Kem{\'e}ny, {Lajos V}",

note = "{\textcopyright} 2024 The Author(s). International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.",

year = "2025",

month = may,

doi = "10.1111/ijd.17586",

language = "English",

volume = "64",

pages = "870--881",

journal = "International journal of dermatology",

issn = "0011-9059",

publisher = "Wiley",

number = "5",

}

Pla, I, Szabolcs, BL, Péter, PN, Ujfaludi, Z, Kim, Y, Horvatovich, P, Sanchez, A, Pawlowski, K, Wieslander, E, Kuras, M, Murillo, JR, Guedes, J, Pál, DMP, Ascsillán, AA, Betancourt, LH, Németh, IB, Gil, J, de Almeida, NP, Szeitz, B, Szadai, L, Doma, V, Woldmar, N, Bartha, Á, Pahi, Z, Pankotai, T, Győrffy, B, Szasz, AM, Domont, G, Nogueira, F, Kwon, HJ, Appelqvist, R, Kárpáti, S, Fenyö, D, Malm, J, Marko-Varga, G & Kemény, LV 2025, 'Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes', International journal of dermatology, vol. 64, no. 5, pp. 870-881. https://doi.org/10.1111/ijd.17586

TY - JOUR

T1 - Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes

AU - Pla, Indira

AU - Szabolcs, Botond L

AU - Péter, Petra Nikolett

AU - Ujfaludi, Zsuzsanna

AU - Kim, Yonghyo

AU - Horvatovich, Peter

AU - Sanchez, Aniel

AU - Pawlowski, Krzysztof

AU - Wieslander, Elisabet

AU - Kuras, Magdalena

AU - Murillo, Jimmy Rodriguez

AU - Guedes, Jéssica

AU - Pál, Dorottya M P

AU - Ascsillán, Anna A

AU - Betancourt, Lazaro Hiram

AU - Németh, István Balázs

AU - Gil, Jeovanis

AU - de Almeida, Natália Pinto

AU - Szeitz, Beáta

AU - Szadai, Leticia

AU - Doma, Viktória

AU - Woldmar, Nicole

AU - Bartha, Áron

AU - Pahi, Zoltan

AU - Pankotai, Tibor

AU - Győrffy, Balázs

AU - Szasz, A Marcell

AU - Domont, Gilberto

AU - Nogueira, Fábio

AU - Kwon, Ho Jeong

AU - Appelqvist, Roger

AU - Kárpáti, Sarolta

AU - Fenyö, David

AU - Malm, Johan

AU - Marko-Varga, György

AU - Kemény, Lajos V

PY - 2025/5

Y1 - 2025/5

N2 - BACKGROUND: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem.OBJECTIVE: Here, we mine large-scale MM proteogenomic data to identify druggable targets and forecast treatment efficacy and resistance.METHODS: Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC, and AKT1, across five distinct MM subtypes. These proteins are potential drug targets applicable to one or multiple MM subtypes. Additionally, by integrating proteogenomic profiles obtained from MM subtypes with MM cell line dependency and drug sensitivity data, we identified a total of 162 potentially targetable genes. Lastly, we identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype.RESULTS: Employing these unbiased approaches, we have uncovered compounds targeting ferroptosis demonstrating a striking 30× fold difference in sensitivity among different subtypes.CONCLUSIONS: Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy.

AB - BACKGROUND: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem.OBJECTIVE: Here, we mine large-scale MM proteogenomic data to identify druggable targets and forecast treatment efficacy and resistance.METHODS: Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC, and AKT1, across five distinct MM subtypes. These proteins are potential drug targets applicable to one or multiple MM subtypes. Additionally, by integrating proteogenomic profiles obtained from MM subtypes with MM cell line dependency and drug sensitivity data, we identified a total of 162 potentially targetable genes. Lastly, we identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype.RESULTS: Employing these unbiased approaches, we have uncovered compounds targeting ferroptosis demonstrating a striking 30× fold difference in sensitivity among different subtypes.CONCLUSIONS: Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy.

U2 - 10.1111/ijd.17586

DO - 10.1111/ijd.17586

M3 - Article

C2 - 39722169

SN - 0011-9059

VL - 64

SP - 870

EP - 881

JO - International journal of dermatology

JF - International journal of dermatology

IS - 5

ER -

Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes

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