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
5595 - Is there any prognostic significance in pleural involvement and/or effusion (Ple-I/E) in patients with ALK-positive NSCLC?
Presenter: Saadettin Kilickap
Session: Poster Display session 1
Resources:
Abstract
5840 - Crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): A European phase 2 clinical trial – Updated progression-free survival, overall survival and mechanisms of resistance
Presenter: Sebastian Michels
Session: Poster Display session 1
Resources:
Abstract
1905 - NTRK1-3 Genomic Fusions in Non-Small Cell Lung Cancer (NSCLC) Determined by Comprehensive Genomic Profiling
Presenter: Sai-Hong Ou
Session: Poster Display session 1
Resources:
Abstract
3016 - Preferential expression of the affected MET allele in lung carcinomas with heterozygous MET exon 14 skipping mutations: implications for clinical testing
Presenter: Evgeny Imyanitov
Session: Poster Display session 1
Resources:
Abstract
4120 - Brain metastases, treatment patterns and outcomes in ROS1-positive NSCLC patients from US oncology community centers
Presenter: Matthew G Krebs
Session: Poster Display session 1
Resources:
Abstract
3764 - Patients with metastatic non-small cell lung cancer and targetable molecular alterations in Germany. Treatment and first outcome data from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Frank Griesinger
Session: Poster Display session 1
Resources:
Abstract
4070 - Crizotinib vs Platinum-based Chemotherapy as First-line Treatment for Advanced Non-small Cell Lung Cancer with Different ROS1 Fusion Variants
Presenter: Haiyan Xu
Session: Poster Display session 1
Resources:
Abstract
5528 - Genomic and clinical characterization of Non-small cell lung cancer (NSCLC) patients harboring mutations in FGFR2 and FGFR3
Presenter: Matthias Scheffler
Session: Poster Display session 1
Resources:
Abstract
3779 - The expression of HER2-gene polymorphisms -1985G>T and P1170A C>G and their association with the risk of development of lung adenocarcinoma
Presenter: Ivan Aleric
Session: Poster Display session 1
Resources:
Abstract
3020 - Circulating tumor DNA (ctDNA) analysis depicts mechanisms of resistance and tumor response to BRAF inhibitors in BRAF-mutant non-small cell lung cancer (NSCLC)
Presenter: Sandra Ortiz - Cuaran
Session: Poster Display session 1
Resources:
Abstract