We are interested in the basic mechanisms that control cell differentiation and proliferation, and their implications in human disease. Adopting a patient-focused perspective, we aim to evaluate the therapeutic opportunities of inhibiting the activity of critical cell cycle regulators in cancer. Inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6), along with hormonotherapy, is the current standard of care in advanced estrogen receptor-positive breast cancer.
However, most metastatic tumors develop resistance, and these inhibitors are not effective in the treatment of other tumor types. Intriguingly, despite extensive cell cycle analysis in the last few years, we still do not understand how cells drive the cell cycle in the absence of CDK4/6 activity. We believe that the CDK family of protein kinases, composed of 20 family members, may provide additional targets not only for tumors with resistance to CDK4/6 inhibitors but also for other pathologies in need of novel therapies. In recent years, we have generated genetic and biochemical tools for the analysis of these drives of proliferation in several tumors types of the breast, liver or lung, as well as gynaecological malignancies.
We are particularly interested in tumors that have lost the control of the cell cycle by altering the retinoblastoma protein (RB1). These mutations are relatively moderate in human cancers (<10%) but are highly relevant in specific tumor types, such as aggressive neuroendocrine carcinomas. How to stop cell proliferation in these aggressive tumor cells is a difficult scientific challenge with important implications for patients with these currently untreatable cancers.
In addition to providing new therapies, we also need to monitor how tumors respond to these treatments more efficiently. We are currently exploring the use of single-cell and spatial genomic and transcriptomic studies to better understand mechanisms of sensitivity and resistance to available therapies. Performing these studies not only in tumoral samples but also in liquid biopsies will facilitate the rapid identification of patients with poor response to available therapies, and the analysis of new actionable mechanisms for future therapies.
- Understand how the balance between proliferation and quiescence or senescence is controlled in physiological conditions.
- Advance insights into the mechanisms of resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors: biomarkers and combinatorial therapies.
- Evaluate novel therapeutic approaches based on cell cycle CDKs as well as unconventional CDKs of unknown function.
- Assess core cell cycle and DNA damage-targeted therapies for patients in progression to current standard-of-care treatments.
- Develop pipelines for monitoring how tumor and immune cells co-evolve in real time in response to cancer treatments.
Group Leader
Marcos Malumbres
Senior Scientist
Begoña Hurtado
Postdoctoral scientists
Isabel García Cao
Alexis Pérez
Elisabeth Aliagas
Aurane Froux
Research Assistants
Raquel Vendrell
Lidia Pérez
Sylwia Radomska
Graduate Students
Gloria C. Bonel
Mariona Cubells
Fátima Guerra
Cristina Molina
Enrique Nogueira
Txinguan Li
Jesús Castillo
Bioinformatician
Agustín Sánchez Belmonte
Simón Bajew
Most relevant publications 2025
- Brandariz J, de Llobet L, Esquefa V, Aguilar D, Salca A, Arce-Gallego S, Cresta Morgado P, Sole A, Agundez L, Mir G, Castro N, Casals T, Oliveira A, Casanova-Salas I, Malumbres M, Carles J, Morellá-Aucejo Á, Bernardos A, Martínez-Máñez R, Mateo J, Herranz N. Harnessing Senolytics and PARP Inhibition to Expand the Antitumor Activity of CDK4/6 Inhibitors in Prostate Cancer. Mol Cancer Ther. 2025 Dec 2;24(12):1959-1976.
- Tolosa P, Pascual T, Martínez-Saez O, Hernando C, Servitja S, Fernández Abad M, Brasó-Maristany F, Sanfeliu E, Benitez Fuentes JD, Lema L, Ruano Y, García-Fructuoso I, Parrilla L, Rodríguez A, Roncero AM, Cobos MÁ, Sánchez-Bayona R, Alva M, Madariaga A, Villacampa G, Canes J, Salvador F, Sánchez-Belmonte A, Malumbres M, Prat A, Ciruelos E. Efficacy outcomes of CDK4/6 inhibitors in combination with endocrine therapy treatment in hormone receptor-positive/HER2-negative advanced breast cancer according to PAM50 intrinsic subtype: Primary results of SOLTI-1801 CDK-PREDICT study. Eur J Cancer. 2025 Feb 25;217:115219.
All Publications
- Lopez-Sainz L, Ayala E, Sánchez-Belmonte A, Ortega E, Caleiras E, Zarzuela E, Isasa M, Santiveri CM, Campos-Olivas R, de Carcer G, Malumbres M (2025) Cyclin Y Overexpression Drives a Fatal Metabolic Syndrome via Defective Glucose Homeostasis. bioRxiv 2025.12.15.694124; doi: 10.64898/2025.12.15.694124.
- Vara-Ciruelos D, Martins AF, El Bakkali A, Sanchez-Belmonte A, Grana-Castro O, Zarzuela E, Isasa M, Salazar-Roa M, Villarroya-Beltri C, Malumbres M (2025) CDC14 phosphatases control adipogenesis via PPARγ de-phosphorylation. bioRxiv 2025.12.13.694119; doi: https://doi.org/10.64898/2025.12.13.694119
- Brandariz J, de Llobet L, Esquefa V, Aguilar D, Salca A, Arce-Gallego S, Cresta Morgado P, Sole A, Agundez L, Mir G, Castro N, Casals T, Oliveira A, Casanova-Salas I, Malumbres M, Carles J, Morellá-Aucejo Á, Bernardos A, Martínez-Máñez R, Mateo J, Herranz N. (2025) Harnessing Senolytics and PARP Inhibition to Expand the Antitumor Activity of CDK4/6 Inhibitors in Prostate Cancer. Mol Cancer Ther 24, 1959-1976. doi: 10.1158/1535-7163.MCT-24-0903. PMID: 40601842.
- Tolosa P, Pascual T, Martínez-Saez O, Hernando C, Servitja S, Fernández Abad M, Brasó-Maristany F, Sanfeliu E, Benitez Fuentes JD, Lema L, Ruano Y, García-Fructuoso I, Parrilla L, Rodríguez A, Roncero AM, Cobos MÁ, Sánchez-Bayona R, Alva M, Madariaga A, Villacampa G, Canes J, Salvador F, Sánchez-Belmonte A, Malumbres M, Prat A, Ciruelos E (2025) Efficacy outcomes of CDK4/6 inhibitors in combination with endocrine therapy treatment in hormone receptor-positive/HER2-negative advanced breast cancer according to PAM50 intrinsic subtype: Primary results of SOLTI-1801 CDK-PREDICT study. Eur J Cancer 217, 115219. doi: 10.1016/j.ejca.2024.115219. PMID: 39779447.
- González-Martínez J, Sánchez-Belmonte A, Ayala A, García A, Nogueira E, Muñoz J, Melati A, Giménez D, Losada A, Ortega S, Malumbres M (2025) miR-203 controls developmental timing and early fate restriction during preimplantation embryogenesis. bioRxiv https://doi.org/10.1101/2024.02.06.579214. Accepted in Sci. Advances, in press.
- Meattini I, Becherini C, Caini S, Coles CE, Cortes J, Curigliano G, de Azambuja E, Isacke CM, Harbeck N, Kaidar-Person O, Marangoni E, Offersen BV, Rugo HS, Salvestrini V, Visani L, Morandi A, Lambertini M, Poortmans P, Livi L, Consensus Panellist Group (incl. Malumbres M). (2024) International multidisciplinary consensus on the integration of radiotherapy with new systemic treatments for breast cancer: European Society for Radiotherapy and Oncology (ESTRO)-endorsed recommendations. Lancet Oncol 25, e73-e83. [PMID: 38301705]
- Vara-Ciruelos D, Malumbres M (2024). Cross Talk Between Metabolism and the Cell Division Cycle. Methods Mol Biol 2740, 141-154. [PMID: 38393474]
- Mayer IM, Doma E, Klampfl T, Prchal-Murphy M, Kollmann S, Schirripa A, Scheiblecker L, Zojer M, Kunowska N, Gebrail L, Shaw LE, Mann U, Farr A, Grausenburger R, Heller G, Zebedin-Brandl E, Farlik M, Malumbres M, Sexl V, Kollmann K. (2024) Kinase-inactivated CDK6 preserves the long-term functionality of adult hematopoietic stem cells. Blood 144, 156-170.. [PMID: 38684032]
- Lorman-Carbó N, Martínez-Sáez O, Fernandez-Martinez A, Galván P, Chic N, Garcia-Fructuoso I, Rodríguez A, Gómez-Bravo R, Schettini F, Blasco P, Castillo O, González-Farré B, Adamo B, Vidal M, Muñoz M, Perou CM, Malumbres M, Gavilá J, Pascual T, Prat A, Brasó-Maristany F (2024) Comparative Biological Activity of Palbociclib and Ribociclib in Hormone Receptor-Positive Breast Cancer. Sci Rep 14, 16030. [PMID: 38992220]
- Sanz-Flores M, Ruiz-Torres M, Aguirre-Portolés C, El Bakkali A, Salvador-Barberó B, Villarroya-Beltri C, Ortega S, Megias D, Gerlich DW, Álvarez-Fernández M, Malumbres M (2024) PP2A-B55 phosphatase counteracts Ki67-dependent chromosome individualization during mitosis. Cell Reports 43, 114494. [PMID: 39003739]
- Malumbres M, Villarroya-Beltri C (2024). Mosaic variegated aneuploidy in development, ageing and cancer. Nat Rev Genet 25, 864-878. doi: 10.1038/s41576-024-00762-6. [PMID: 39169218]
- Cano A, Yubero ML, Millá C, Puerto-Belda V, Ruz JJ, Kosaka PM, Calleja M, Malumbres M. Tamayo J. (2024) Rapid mechanical phenotyping of breast cancer cells based on stochastic intracellular fluctuations. iScience 27, 110960. [PMID: 39493877]
- Villarroya-Beltri C, Martins AFB, García A, Giménez D, Zarzuela E, Novo M, Del Álamo C, González-Martínez J, Bonel-Pérez GC, Díaz I, Guillamot M, Chiesa M, Losada A, Graña-Castro O, Rovira M, Muñoz J, Salazar-Roa M, Malumbres M. (2023) Mammalian CDC14 phosphatases control exit from stemness in pluripotent cells. EMBO J. 42, e111251. doi: 10.15252/embj.2022111251. [PMID: 36326833]
- Sanz-Castillo B, Hurtado B, Vara-Ciruelos D, El Bakkali A, Hermida D, Salvador-Barbero B, Martínez-Alonso D, González-Martínez J, Santiveri C, Campos-Olivas R, Ximénez-Embún P, Muñoz J, Álvarez-Fernández M, Malumbres M. (2023) The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner. EMBO J. 42, e110833. doi: 10.15252/embj.2022110833. [PMID: 36354735]
- Olivera-Salguero R, Seguí E, Cejalvo JM, Oliveira M, Tolosa P, Vidal M, Malumbres M, Gavilá J, Saura C, Pernas S, López R, Margelí M, Balmaña J, Muñoz M, Blancas I, Boni V, Ciruelos E, Galve E, Perelló A, Sánchez-Bayona R, de la Cruz S, de la Hoya M, Galván P, Sanfeliu E, Gonzalez-Farre B, Sirenko V, Blanch-Torras A, Canes J, Masanas H, Olmos R, Forns M, Prat A, Casas A*, Pascual T* (2023) HOPE (SOLTI-1903) Breast Cancer Study: Real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer. Front Oncol 13:1151496. [PMID: 37188177]
- Martínez-Illescas NG, Leal S, González P, Graña-Castro O, Muñoz-Oliveira JJ, Cortés-Peña A, Gómez-Gil M, Vega Z, Neva V, Romero A, Quintela-Fandino M, Ciruelos E, Sanz C, Aragón S, Sotolongo L, Jiménez S, Caleiras E, Mulero F, Sánchez C*, Malumbres M*, Salazar-Roa M*. (2023) miR-203 drives breast cancer cell differentiation. Breast Cancer Res 25:91. doi: 10.1186/s13058-023-01690-9. [PMID: 37542268]
- Frontiñán-Rubio J, Llanos-González E, García-Carpintero S, Peinado JR, Ballesteros-Yáñez I, Rayo MV, de la Fuente J, Pérez-García VM, Perez-Romasanta LA, Malumbres M, Alcaín FJ, Durán-Prado M. (2023) CoQ10 reduces glioblastoma growth and infiltration through proteome remodeling and inhibition of angiogenesis and inflammation. Cell Oncol 46, 65-77. doi: 10.1007/s13402-022-00734-0. [PMID: 36319818]
- Dhital B, Santasusagna S, Kirthika P, Xu M, Li P, Carceles-Cordon M, Soni RK, Li Z, Hendrickson RC, Schiewer MJ, Kelly WK, Sternberg CN, Luo J, Lujambio A, Cordon-Cardo C, Alvarez-Fernandez M, Malumbres M, Huang H, Ertel A, Domingo-Domenech J, Rodriguez-Bravo V. (2023) Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer. Cell Rep Med. 4, 100937. doi: 10.1016/j.xcrm.2023.100937. [PMID: 36787737]
- Mouron S, Bueno MJ, Muñoz M, Torres R, Rodríguez S, Apala JV, Silva J, Sánchez-Bayona R, Manso L, Guerra J, Rodriguez-Lajusticia L, Malon D, Malumbres M, Quintela-Fandino M. (2023) p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer. JNCI Cancer Spectr. Feb 20:pkad014. doi: 10.1093/jncics/pkad014. [PMID: 36806942]
- Sayago C, Sánchez-Wandelmer J, García F, Hurtado B, Lafarga V, Prieto P, Zarzuela E, Ximénez-Embún P, Ortega S, Megías D, Fernández-Capetillo O, Malumbres M, Munoz J. (2023) Decoding protein methylation function with thermal stability analysis. Nat Commun. 14, 3016. [PMID: 37230995] doi: 10.1038/s41467-023-38863-1.
- Baldrighi, M., Doreth, C., Li, Y., Zhao, X., Warner, E., Chenoweth, H., Kishore, K., Umrania, Y., Minde, D.P., Thome, S., Yu, X., Lu, Y., Knapton, A., Harrison, J., Clarke, M., Latz, E., de Carcer, G., Malumbres, M., Ryffel, B., Bryant, C., Liu, J., Lilley, K.S., Mallat, Z., Li, X. (2023) PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models. J Clin Invest 133, e162129. [PMID: 37698938]
- HOPE (SOLTI-1903) breast cancer study: real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer. Olivera-Salguero R, Seguí E, Cejalvo JM, Oliveira M, Tolosa P, Vidal M, Malumbres M, Gavilá J, Saura C, Pernas S, López R, Margelí M, Balmaña J, Muñoz M, Blancas I, Boni V, Ciruelos E, Galve E, Perelló A, Sánchez-Bayona R, de la Cruz S, de la Hoya M, Galván P, Sanfeliu E, Gonzalez-Farre B, Sirenko V, Blanch-Torras A, Canes J, Masanas H, Olmos R, Forns M, Prat A, Casas A, Pascual T. Front Oncol. 2023 Apr 28;13:1151496. doi: 10.3389/fonc.2023.1151496. eCollection 2023.https://pubmed.ncbi.nlm.nih.gov/37188177/
- Decoding protein methylation function with thermal stability analysis.Sayago C, Sánchez-Wandelmer J, García F, Hurtado B, Lafarga V, Prieto P, Zarzuela E, Ximénez-Embún P, Ortega S, Megías D, Fernández-Capetillo O, Malumbres M, Munoz J. Nat Commun. 2023 May 25;14(1):3016. doi: 10.1038/s41467-023-38863-1.https://pubmed.ncbi.nlm.nih.gov/37230995/
- (2023) Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer. Cell Rep Med. Feb 7:100937. [Pubmed]
- Mouron S, Bueno MJ, Muñoz M, Torres R, Rodríguez S, Apala JV, Silva J, Sánchez-Bayona R, Manso L, Guerra J, Rodriguez-Lajusticia L, Malon D, Malumbres M, Quintela-Fandino M. p27Kip1 V109G as a biomarker for CDK4/6 inhibitors indication in hormone receptor-positive breast cancer. JNCI Cancer Spectr. 2023 Mar 1;7(2):pkad014. doi: 10.1093/jncics/pkad014. PMID: 36806942; PMCID: PMC10035773.
(all of them are also here: https://malumbreslab.org/publications/)
Unlocking Drugability of Tumor-Driving Transcription Factors: Development of NTX-A, a First-in-Class Drug Targeting the ASCL1 Disordered Domain for Small Cell Lung Cancer. Funded by: Agencia Estatal de Investigación – Ministerio de Ciencia, Innovación y Universidades. CPP2024-011304. 01/10/2025 – 30/09/2028. Coordinator: Nuage Therapeutics, S.L. PI VHIO: Marcos Malumbres
Retinoblastoma Protein and Neuroendocrine Transformation in Lung Cancer (NE-RB1)
Funded by: Agencia Estatal de Investigación – Ministerio de Ciencia e Innovación
Reference: PID2024-161681OB-I00
Execution period: 01/09/2025 – 31/08/2028
PI: Marcos Malumbres
Targeting CDK16-18 as a novel strategy against aggressive cancers (neoCDK)
PI: M. Malumbres.
A new platform to predict response to CDK4/6 inhibitors in metastatic breast cancer patients
Reference: DTS21/00132
Ministerio de Ciencia e Innovación
Award Period: 01/2022-12/2023.
PI: M. Malumbres.
Proliferación y diferenciación celular: mecanismos y relevancia patológica
Funded by: MCIN/AEI/10.13039/501100011033
Ref: RED2024-153635-T
Period: 01/05/2025 – 31/04/2027
Coordinator: Marcos Malumbres
Therapeutic evaluation of the Cdk14-18 subfamily in advanced breast cancer (breastCDKS)
Reference: PID2021-128726OB-I00
Ministerio de Ciencia, Innov. y Univ.
Award Period: 1/2022-31/2024
IP: M. Malumbres.
Implementing CDK16-18 targeted therapies for cancer treatment
PDC2022-133408-I00
Ministerio de Ciencia, Innov. y Univ.
Award Period: 1/2023-31/2024
IP: M. Malumbres.
Balancing cell proliferation and differentiation: mechanisms and relevance in human disease
Títle: Predictive spatial transcriptomics to identify minimal residual in ER+ HER2 – breast cancer
Grantor: Asociación de Cancer de Mama Metastásico.
Duration: 1/12/2023-30/11/2025
PI: Marcos Malumbres
CDK6: an unexpected culprit in the lack of response to CDK4/6 inhibitors in progressive breast cancer
Funding body: FERO Oncology Research Foundation
Reference: PFERO2023.02
Project period: 01/01/2024 – 31/12/2025
Principal Investigator (PI): Marcos Malumbres
Predictive spatial transcriptomics to identify minimal residual disease in ER+ HER2- breast cancer
Funding body: Spanish Association for Metastatic Breast Cancer (AECMM)
Reference: 5th Call – M. Chiara Giorgetti Award for Research in Metastatic Breast Cancer
Project period: 01/12/2023 – 30/11/2025
Principal Investigator (PI): Marcos Malumbres
CDK14–18: the next generation of CDK-targeted therapies
Funding body: AstraZeneca Farmacéutica Spain S.A.
Reference: 10050671
Project period: 14/06/2022 – 13/06/2026
Principal Investigator (PI): Marcos Malumbres
Orphan CDKs as novel therapeutic targets in cancer
Funding body: Ministry of Science, Innovation and Universities
Reference: DTS24/00099
Project period: 2024 – 2026
Principal Investigator (PI): Marcos Malumbres
SOSCLC – AECC: Small Cell Lung Cancer. From biological networks to personalized therapy
Funding body: Scientific Foundation of the Spanish Association Against Cancer (AECC)
Reference: RETOS245794PAZA
Project period: 01/07/2024 – 30/06/2029
Project Coordinator: Marcos Malumbres
Unlocking the druggability of tumor-driving transcription factors: development of NTX-A, a first-in-class drug targeting the ASCL1 disordered domain for Small Cell Lung Cancer
Funding body: Spanish State Research Agency
Reference: CPP2024-011304
Project period: 01/10/2025 – 30/09/2028
Project Coordinator: Marcos Malumbres
