Functional Deconstruction of AC-T Chemotherapy Reveals Interindividual Heterogeneity and Independent Drug Action in Breast Cancer.

@article{simoes2026functional,
  title = {{Functional Deconstruction of AC-T Chemotherapy Reveals Interindividual Heterogeneity and Independent Drug Action in Breast Cancer.}},
  author = {Lucas Damé Simões and Giulia Luiza Santos and Priscila Oliveira de Carvalho and Ernande Xavier Dos Santos and Amanda Rafaela Alves Canteli and Ronaldo Morales Junior and Carolina Rossi Saccarelli and Larissa Assad João Moysés and Ligia Akemi Yamashita and Patricia Akissue de Camargo Teixeira and Thiago Yoshio Kobayashi and Vera Christina Camargo de Siqueira Ferreira and Vivian Larissa Nakamura Omura and Luma Soares de Almeida and Carlos Henrique Dos Anjos and Alfredo Carlos S D de Barros and Anamaria Aranha Camargo and José Luiz B Bevilacqua and Daniela G Giannotti and Érico Tosoni Costa},
  journal = {Cancers},
  year = {2026},
  month = sep,
  doi = {10.3390/cancers18193121},
  url = {https://europepmc.org/article/MED/42882816},
  note = {CC BY},
}

TY  - JOUR
TI  - Functional Deconstruction of AC-T Chemotherapy Reveals Interindividual Heterogeneity and Independent Drug Action in Breast Cancer.
AU  - Lucas Damé Simões
AU  - Giulia Luiza Santos
AU  - Priscila Oliveira de Carvalho
AU  - Ernande Xavier Dos Santos
AU  - Amanda Rafaela Alves Canteli
AU  - Ronaldo Morales Junior
AU  - Carolina Rossi Saccarelli
AU  - Larissa Assad João Moysés
AU  - Ligia Akemi Yamashita
AU  - Patricia Akissue de Camargo Teixeira
AU  - Thiago Yoshio Kobayashi
AU  - Vera Christina Camargo de Siqueira Ferreira
AU  - Vivian Larissa Nakamura Omura
AU  - Luma Soares de Almeida
AU  - Carlos Henrique Dos Anjos
AU  - Alfredo Carlos S D de Barros
AU  - Anamaria Aranha Camargo
AU  - José Luiz B Bevilacqua
AU  - Daniela G Giannotti
AU  - Érico Tosoni Costa
PY  - 2026
DA  - 2026/09/26
JO  - Cancers
DO  - 10.3390/cancers18193121
UR  - https://europepmc.org/article/MED/42882816
AB  - Background/Objectives: Combination chemotherapy remains a cornerstone of breast cancer (BC) treatment, yet the relative contribution of individual drugs within standard regimens remains poorly understood. We investigated whether the activity of the widely used anthracycline-cyclophosphamide-taxane (AC-T) regimen reflects uniform benefit from all constituent drugs or heterogeneous drug-specific vulnerabilities across tumors. Methods: We combined in silico drug-response analyses, functional validation in BC cell lines, and ex vivo profiling in patient-derived organoids (PDOs). Drug responses were integrated into the Probability of Chemotherapeutic Efficacy (PCE), a multidimensional response metric combining relative drug potency, maximal efficacy, and clinically achievable free-drug exposure. To explore the broader applicability of PCE, we additionally applied it to an independent publicly available GR-based pharmacological dataset generated by the HMS LINCS Center. Results: Across BC models, anthracyclines and taxanes displayed only partially overlapping sensitivity profiles, indicating distinct drug-specific vulnerabilities. Functional validation in 2D cell lines and PDOs confirmed highly context-dependent responses to AC-T components. Among 21 PDOs with complete drug-response datasets, extensive interpatient heterogeneity was observed, with non-overlapping patterns of sensitivity to A, C, and T. Responses were better represented as a continuum of functional vulnerability states than as binary sensitive-versus-resistant categories. AC generated the highest proportion of favorable response profiles, with 62% of PDOs classified as partial response-like or complete response-like, compared with 48% for A, 38% for C, and 14% for T. AC activity was positively associated with the most active constituent drug within each PDO. Application of this framework to an independent public dataset produced biologically plausible response patterns consistent with the molecular characteristics of the evaluated breast cancer cell lines, supporting its computational transferability. Conclusions: These findings reveal substantial heterogeneity in the contribution of individual drugs to AC-T activity and are compatible with a model in which different tumors derive benefit from different regimen components. Together, these findings establish a hypothesis-generating functional framework for dissecting the contribution of individual drugs within combination chemotherapy regimens. Prospective studies correlating PDO-derived functional responses with clinical outcomes will be required to determine the predictive value and potential clinical utility of this approach before informing therapeutic decision-making.
SN  - 2072-6694
ER  -