Abstract 1735
Background
Breast cancer is the malignant neoplasm with the highest incidence and mortality in women worldwide. Approximately 70% of breast tumors express hormone receptors (HR+). Although antiestrogen tamoxifen has been successful for HR+ breast cancer treatment, a significant amount of these tumors eventually develop resistance. In these cases, the addition of CDK4/6 inhibitor palbociclib has shown clinical effectiveness. However, there is still a need to elucidate the mechanisms underlying resistance to these treatments in order to design better combination therapies for each case and improve patient outcomes. The aim of this work was to study these mechanisms using cell variants generated to mimic what occurs in the clinic.
Methods
We developed three cell lines with acquired resistance to tamoxifen (T47D-TR), palbociclib (T47D-PR) and tamoxifen+palbociclib (T47D-TPR), by exposing T47D wild type cells to progressively increasing concentrations of the drugs over a period of about 12 months.
Results
Western blot analysis showed decreased levels of HR, higher activation levels of PI3K/Akt/mTOR pathway, along with greater levels of cell cycle associated proteins in all resistant cell lines. The resistant tumors generated as xenografts in immunosuppressed mice showed more invasive characteristics than those generated from the T47D-wt cell line, despite the lower growth rates showed by all resistant lines. Finally, we analyzed the response to palbociclib and to PI3K/Akt/mTOR inhibitors in the resistant cell lines. We found that all resistant lines were sensitive to BKM-120 (PI3K inhibitor) and to rapamycin (mTOR inhibitor), and the combination with palbociclib showed an additive inhibitory effect in both cases. However, the sensitivity of the resistant cells was greater to rapamycin than to BKM-120.
Conclusions
Taken together, our results support the use of mTOR inhibitors, rather than PI3K inhibitors, in combination with CDK4/6 inhibitors in the treatment of both tamoxifen and palbociclib resistant tumors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
FONCYT-INC-CONICET.
Funding
FONCYT-INC-CONICET.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5519 - Is there a difference of Palliative care problems and needs between cancer and non-cancer hospitalized elderly patients?
Presenter: Ioanna Chatzi
Session: Poster Display session 1
Resources:
Abstract
2505 - There is a lack of clinical research for patients with cancer in palliative care
Presenter: Marie Vinches
Session: Poster Display session 1
Resources:
Abstract
5273 - Specialist Palliative Care (SPC) in Haematological Malignancy: Establishing practices in a UK Tertiary Cancer Centre (TCC)
Presenter: Emma Kedgley
Session: Poster Display session 1
Resources:
Abstract
5864 - Evaluation of the relationship between the attachment styles and psychological resilience of cancer patients receiving chemotherapy
Presenter: Fatma Bugdayci Basal
Session: Poster Display session 1
Resources:
Abstract
770 - Gefitinib along with Methotrexate as palliative therapy in PS 3 and above in metastatic squamous cell carcinoma head and neck cancer patients
Presenter: Vidya Dusi
Session: Poster Display session 1
Resources:
Abstract
4232 - High intensity end-of-life care in pediatrics, adolescent and young adult patients with cancer using an administrative database.
Presenter: Seiko Bun
Session: Poster Display session 1
Resources:
Abstract
4845 - Embedded outpatient palliative care service within the oncology clinic: Preliminary experience in Hacettepe Oncology Hospital
Presenter: Deniz Can Guven
Session: Poster Display session 1
Resources:
Abstract
3270 - Internet-based stepped care for individuals with cancer and concurrent anxiety or depression symptoms – results from a randomized controlled trial
Presenter: Birgitta Johansson
Session: Poster Display session 1
Resources:
Abstract
5503 - Impact of Cognitive-Behavioral-Therapy (CBT) on levels of anxiety, depression and distress in cancer patients (pts)
Presenter: Daniela Tregnago
Session: Poster Display session 1
Resources:
Abstract
5553 - Cytokine genetic variations and worse quality of life among family caregivers of head and neck cancer patients in palliative care
Presenter: Daniel Pequeno
Session: Poster Display session 1
Resources:
Abstract