Inhibition of PTCH1 drug efflux activity enhances chemotherapy efficacy against triple negative breast cancers
Abstract
Our previous work has revealed that PTCH1, a Hedgehog receptor which is expressed in many aggressive cancers, plays a role in transporting chemotherapeutic drugs out of cancer cells and contributes to their resistance to chemotherapy. PTCH1 transports drugs via the proton motive force using the 'reverse pH gradient', which makes its drug efflux activity specific to cancer cells and PTCH1 a highly relevant and specific new therapeutic target for cancer treatment. We have identified a small molecule produced by a marine sponge as being able to inhibit PTCH1 efflux activity and increase the efficacy of vemurafenib treatment on BRAF-mutated melanoma cells in vitro and in vivo in mice. In the present study, we demonstrate the presence of PTCH1 mRNA in tumour samples and circulating tumour cells from breast cancer patients, particularly those with triple-negative breast cancer (TNBC). TNBC is the most aggressive breast cancer subtype, characterised by a high risk of resistance to chemotherapy and a high potential for relapse. Our analyses reveal that high levels of PTCH1 mRNA are associated with a poor prognosis in TNBC patients. We found that inhibiting PTCH1 drug efflux activity significantly increased the cytotoxic effect of chemotherapies such as doxorubicin and docetaxel in three TNBC cell lines. Overall, our findings suggest that PTCH1 plays a role in the resistance of TNBC cells to chemotherapy, and that using a PTCH1 efflux inhibitor during neoadjuvant or adjuvant therapy could enhance the efficacy of treatment against PTCH1-expressing TNBC, while preventing treatment resistance, relapse, and metastasis formation.
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BibTeX
@article{cogoluegnes2026inhibition,
title = {{Inhibition of PTCH1 drug efflux activity enhances chemotherapy efficacy against triple negative breast cancers}},
author = {Sarah Cogoluegnes and Sandra Kovachka and Thierry Dubois and Roberto Würth and Elisa Donato and Andreas Trumpp and Michel Franco and Frédéric Luton and Stéphane Azoulay and Isabelle Mus-Veteau},
journal = {Translational Oncology},
year = {2026},
month = sep,
doi = {10.1016/j.tranon.2026.102777},
url = {https://hal.science/hal-05768643v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Inhibition of PTCH1 drug efflux activity enhances chemotherapy efficacy against triple negative breast cancers
AU - Sarah Cogoluegnes
AU - Sandra Kovachka
AU - Thierry Dubois
AU - Roberto Würth
AU - Elisa Donato
AU - Andreas Trumpp
AU - Michel Franco
AU - Frédéric Luton
AU - Stéphane Azoulay
AU - Isabelle Mus-Veteau
PY - 2026
DA - 2026/09/29
JO - Translational Oncology
DO - 10.1016/j.tranon.2026.102777
UR - https://hal.science/hal-05768643v1
AB - Our previous work has revealed that PTCH1, a Hedgehog receptor which is expressed in many aggressive cancers, plays a role in transporting chemotherapeutic drugs out of cancer cells and contributes to their resistance to chemotherapy. PTCH1 transports drugs via the proton motive force using the 'reverse pH gradient', which makes its drug efflux activity specific to cancer cells and PTCH1 a highly relevant and specific new therapeutic target for cancer treatment. We have identified a small molecule produced by a marine sponge as being able to inhibit PTCH1 efflux activity and increase the efficacy of vemurafenib treatment on BRAF-mutated melanoma cells in vitro and in vivo in mice. In the present study, we demonstrate the presence of PTCH1 mRNA in tumour samples and circulating tumour cells from breast cancer patients, particularly those with triple-negative breast cancer (TNBC). TNBC is the most aggressive breast cancer subtype, characterised by a high risk of resistance to chemotherapy and a high potential for relapse. Our analyses reveal that high levels of PTCH1 mRNA are associated with a poor prognosis in TNBC patients. We found that inhibiting PTCH1 drug efflux activity significantly increased the cytotoxic effect of chemotherapies such as doxorubicin and docetaxel in three TNBC cell lines. Overall, our findings suggest that PTCH1 plays a role in the resistance of TNBC cells to chemotherapy, and that using a PTCH1 efflux inhibitor during neoadjuvant or adjuvant therapy could enhance the efficacy of treatment against PTCH1-expressing TNBC, while preventing treatment resistance, relapse, and metastasis formation.
SN - 1944-7124
SN - 1936-5233
ER -