43P - AKT and estrogen receptor (ER) inhibition potently impairs endocrine resistance (EndoR) in breast cancer (BC)

Background

The PI3K/AKT/mTOR and MEK/MAPK pathways are suggested mechanisms of EndoR. However, single kinase inhibitors (Ki), like everolimus, only partially reverse EndoR, probably due to activation of adaptive pathways. We previously showed that combining fulvestrant (Ful) + AKT inhibitor (AKTi, Capivasertib) reversed tamoxifen resistant (TamR) in vivo tumor growth and that adding a MEKi (Selumetinib) to either AKTi or mTORi (Vistusertib) further enhanced growth inhibition. Here, in a 2^nd study, we aimed to reassess the potency of the Ki with an adjusted 33% reduced AKTi dose and to explore the signaling modulation underlying these effects.

Methods

In this study we used an aggressive later generation of the transplantable ER+ MCF7/TamR xenograft model, testing the effect of the Ki alone or in combination (Ki combo: mTORi+MEKi, AKTi+MEKi) on tumor growth and signaling in the presence of Ful after short term (ST, 1 week) and long term (LT) treatment (as tumors progressed to ∼ 1000mm³ in size or at the end of the study, ∼ 130 days). Reverse phase protein array (RPPA; with 172 anti-phospho/total antibodies) was used to profile the signaling landscape of different Kis in the presence of Ful after ST (2^nd study) or LT (both studies) treatment.

Results

Lower dose AKTi and mTORi single Ki inhibited tumor growth. RPPA analysis showed on-target activity of single and Ki combo after ST and LT treatment. While MEKi, consistent with its lack of effect on tumor growth, did not show any further signaling modulation, AKTi and mTORi affected multiple signaling components. Ki combo with MEKi enhanced the effect on signaling and tumor growth, though, in the 2^nd study, the effect on the latter was significant only with mTORi. Among the modulated factors in the mTORi and AKTi containing treatments, pSTAT6 was upregulated by both ST and LT treatments, possibly as an adaptive/resistant mechanism. Of note, diverse integrin and tyrosine kinases receptor members were upregulated by LT treatment with the Ki combo, potentially as escape pathways.

Conclusions

Our findings support the role of AKT/mTOR in EndoR BC and the clinical development of potent ER inhibitors plus AKTi to overcome it. Additional studies exploring Ki combo to counter adaptive and resistant signaling are warranted.

Legal entity responsible for the study

The authors.

Funding

AstraZeneca.

Disclosure

G. Morrison-Thiele: Financial Interests, Personal, Full or part-time Employment: AbbVie. A. Goldstein: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals. C. De Angelis: Financial Interests, Personal, Advisory Board: Roche, Eli Lilly, GSK, Novartis, Pfizer, AstraZeneca; Financial Interests, Institutional, Funding: Novartis. X. Fu: Financial Interests, Personal, Full or part-time Employment: Gilead. S. Cosulich: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. B. Davies: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. R. Jeselsohn: Financial Interests, Institutional, Research Grant: Pfizer, Eli Lilly; Financial Interests, Personal, Advisory Board: Carrick Therapeutics, GE Health. L. Malorni: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Seagen; Financial Interests, Personal and Institutional, Research Grant: Novartis, Pfizer. M. Rimawi: Financial Interests, Personal, Advisory Board, Consulting: Genentech, Novartis, AstraZeneca, Seagen; Financial Interests, Personal, Advisory Board, Advisory Board: Macrogenics; Financial Interests, Institutional, Research Grant: Pfizer. C.K. Osborne: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Stocks/Shares: GeneTex. R. Schiff: Financial Interests, Personal, Advisory Board: MacroGenics; Financial Interests, Institutional, Research Grant: Puma Biotechnology, Gilead Sciences; Financial Interests, Personal, Royalties: Wolters Kluwer/UpToDate; Financial Interests, Institutional, Other: PCT Patent. All other authors have declared no conflicts of interest.