New class of drugs show promise for ER+ endocrine therapy reisistant bc

[Hopeful]

http://breast-cancer-research.com/co...df/bcr2833.pdf

Hopeful

[Rich66]

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Conclusions focused on the induction of
apoptosis because the ability of PI3K inhibitors to induce cell death, rather than inhibit cell
proliferation, is considered to be the best predictor of in vivo anti-tumor response [17]. The dual
PI3K/mTOR inhibitor BGT226 generally produced the highest levels of apoptosis when
combined with estrogen deprivation in sensitive cells, followed by the PI3K isoform selective
inhibitor BKM120. In contrast, the level of apoptosis induced by the mTOR-selective inhibitor
RAD001 in estrogen-deprived cells was modest by comparison, even in the most sensitive cells.
Poor induction of apoptosis by RAD001 in estrogen-deprived ER+ cells is consistent with the
results of a randomized Phase 2 trial (NCT00107016) that evaluated the efficacy of the
aromatase inhibitor letrozole and RAD001 as neoadjuvant treatment for ER+ breast cancer.
Despite greater inhibition of tumor proliferation, the pathological complete response (pCR) rate
was not increased by RAD001 over that observed using letrozole alone suggesting no clinically
significant increase in cell death was achieved [23]. Our data suggests that if tolerable at active
doses, direct inhibitors of PI3K might be more effective in this setting.
The sensitizing effect of PIK3CA mutation to the dual PI3K/mTOR inhibitor BEZ235 and to a
selective Akt inhibitor in breast cancer cells has already been reported [9, 17]. However these
studies included few PIK3CA wild-type ER+ HER2- cells and it was not clear how PIK3CA
mutation impacts PI3K inhibitor sensitivity in the setting of estrogen-deprivation. Our data
supports the conclusion that PIK3CA mutation confers sensitivity to PI3K pathway inhibitors in
the setting of new agents in clinical development and that this differential effect is maintained
under estrogen-deprived conditions. However, the impact of estradiol on PI3K pathway inhibitor
activity in PIK3CA mutant cells was not uniform. Estradiol suppressed apoptosis induced by
BGT226 in MCF7 and T47D cells but not in BT-483 cells. The identification of additional
biomarkers will be therefore likely necessary to fully predict the efficacy of PI3K/endocrine
combination therapy in PIK3CA mutant ER+ tumors. Consistent with previous reports, the
effect of PTEN mutation on the sensitivity of ER+ cells to PI3K inhibitors also appears complex
[9, 17]. Whereas the PTEN-negative MDA-MB-415 and ZR75-1 lines were sensitive to both
BGT226 and BKM120, the CAMA-1 line, which is PTEN mutant, but does express low amounts
of PTEN, was resistant to both inhibitors. The reasons for the inconsistent effects of PTEN
deficiency on PI3K pathway inhibitor sensitivity in ER+ cells will also require further study.
Estradiol is thought to prevent apoptosis through plasma membrane-initiated or “non-genomic”
signaling by the ER through activation of the PI3K and MAP kinase pathways [24, 25].
Consistent with these reports, our results indicate that transduction of the estradiol survival signal
increases PI3K inhibitor dose requirements in some ER+ breast cancer cells (e.g., MCF7 and
T47D cells) but not others (BT-483, MDA-MB-415 and ZR75-1 cells). Interestingly, our results
also show that the anti-apoptotic activity of estradiol is preserved in breast cancer cells that do
not require estradiol for proliferation as a consequence of prolonged estrogen deprivation (Figure
6). The decoupling of the proliferative and anti-apoptotic effects of estrogen suggests that
continuing estrogen deprivation in progressing patients and adding a PI3K inhibitor might be a
strategy worth testing.
The optimal endocrine combination with PI3K inhibition in cells resistant to estrogen deprivation
is a critical consideration since the overwhelming majority of patients with advanced breast
cancer have already been treated with an aromatase inhibitor in the adjuvant setting. Treatment
options include an anti-estrogen (such as the ER down-regulator fulvestrant) [26] or therapy with
low-dose estradiol [21]. We modeled these second-line approaches in contrasting LTED cell
lines, one where ER expression was maintained and one where it was lost, in order to reflect the
clinical observation that upon disease progression ER is down-regulated in a proportion of cases
[27, 28]. Both LTED lines were found to be relatively resistant to PI3K inhibitors compared to
the parental lines, consistent with reports that acquiring the ability to grow in the absence of
estrogen is associated with increases PI3K and MAP kinase signaling [29]. However, the use of
fulvestrant efficiently sensitized MCF7 LTED cells to both BKM120 and BGT226, consistent
with a key role for ligand-independent ER activity in PI3K inhibitor resistance. The use of
estradiol to revert the LTED phenotype, followed by re-institution of estrogen deprivation is a
viable alternative strategy, however, the restoration of sensitivity to PI3K inhibition with this
approach appeared less profound than with fulvestrant treatment.
Taken together our data provide rationale for combining estrogen deprivation with PI3K
inhibitors for the treatment of PIK3CA mutant, estrogen-dependent ER+ tumors and for the
combination of fulvestrant with PI3K inhibitors in patients with ER+, aromatase inhibitorresistant
disease. However, further studies will be necessary