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.
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.
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.
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.
FONCYT-INC-CONICET.
FONCYT-INC-CONICET.
All authors have declared no conflicts of interest.