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
1851 - Nivolumab-induced and radiation recall pneumonitis in patients with non-small cell lung cancer: a multicenter real world analysis of 669 patients
Presenter: Nobuaki Mamesaya
Session: Poster Display session 1
Resources:
Abstract
851 - Retrospective analysis of immunotherapy prognostic scores in advanced NSCLC at Nottingham University Hospitals (UK)
Presenter: Cristina Lopez Escola
Session: Poster Display session 1
Resources:
Abstract
3639 - Applicability of lung immune prognostic index (LIPI) to predict efficacy of first-line pembrolizumab in advanced non-small-cell lung cancer (NSCLC)
Presenter: Xabier Mielgo Rubio
Session: Poster Display session 1
Resources:
Abstract
2950 - Delayed Onset Immune Related Adverse Effects (IRAEs) of Pembrolizumab in Non-Small Cell Lung Cancer
Presenter: Haixi Yan
Session: Poster Display session 1
Resources:
Abstract
3659 - Clinical implication of multiplex IHC and serologic biomarkers on Hyperprogression in NSCLC patients receiving Immune checkpoint blockers in real world.
Presenter: Joori Kim
Session: Poster Display session 1
Resources:
Abstract
4882 - Local ablative treatment and treatment beyond progression for oligo-progression in stage IV non-small cell lung cancer after tumor response to anti-PD1 treatment
Presenter: Florian Guisier
Session: Poster Display session 1
Resources:
Abstract
1358 - Atezolizumab in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs)
Presenter: Francis Mogollon-Duffo
Session: Poster Display session 1
Resources:
Abstract
2170 - Prognostic Impact of Metastatic Sites for Pembrolizumab Efficacy as First-line therapy in Patients with PD-L1 tumor proportion score (TPS) ≥ 50% Advanced Non–Small Cell Lung Cancer: A Retrospective Multicenter Study
Presenter: Hayato Kawachi
Session: Poster Display session 1
Resources:
Abstract
3051 - Impact of visceral fat area as independent predictive factor in patients with advanced non-small cell lung cancer treated with nivolumab
Presenter: Yuki Sato
Session: Poster Display session 1
Resources:
Abstract
3409 - Effect and safety of immune checkpoint inhibitors for brain metastases from non-small cell lung cancer
Presenter: Toshihiko Iuchi
Session: Poster Display session 1
Resources:
Abstract