Targeting mTOR pathway inhibits tumor growth in different molecular subtypes of triple-negative breast cancers

Abstract

Triple-negative breast cancers (TNBC) are characterized by frequent alterations in the PI3K/AKT/mTOR signaling pathway. In this study, we analyzed PI3K pathway activation in 67 patient-derived xenografts (PDX) of breast cancer and investigated the anti-tumor activity of the mTOR inhibitor everolimus in 15 TNBC PDX with different expression and mutational status of PI3K pathway markers.Expression of the tumor suppressors PTEN and INPP4B was lost in 55% and 76% of TNBC PDX, respectively, while mutations in PIK3CA and AKT1 genes were rare. In 7 PDX treatment with everolimus resulted in a tumor growth inhibition higher than 50%, while 8 models were classified as low responder or resistant. Basal-like, LAR (Luminal AR), mesenchymal and HER2-enriched tumors were present in both responder and resistant groups, suggesting that tumor response to everolimus is not restricted to a specific TNBC subtype. Analysis of treated tumors showed a correlation between tumor response and post-treatment phosphorylation of AKT, increased in responder PDX, while PI3K pathway markers at baseline were not sufficient to predict everolimus response.In conclusion, targeting mTOR decreased tumor growth in 7 out of 15 TNBC PDX tested. Response to everolimus occurred in different TNBC subtypes and was associated with post-treatment increase of P-AKT.

A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

“…This pathway was particularly altered in LAR, BL2 and MSL subtypes, as described in several other studies and inhibitors of this pathway could be useful in these particular subtypes. We have previously shown that everolimus induced a significant response in 7 out of 15 TNBC PDX, irrespective of the PIK3CA mutational status . In another study, seven TNBC PDX treated with rapamycin (mTOR inhibitor), showed a marked growth inhibition, supporting the value of this treatment in TNBC .…”

“…We have previously shown that everolimus induced a significant response in 7 out of 15 TNBC PDX, irrespective of the PIK3CA mutational status. 38 In another study, seven TNBC PDX treated with rapamycin (mTOR inhibitor), showed a marked growth inhibition, supporting the value of this treatment in TNBC. 39 Few clinical data are available concerning the PI3K pathway inhibitor in TNBC 40 and various studies have tested specific PI3K inhibitors and have tried to identify biomarkers (SAFIR study, NCT02299999).…”

Targeted therapies in breast cancer: New challenges to fight against resistance

“…The mTOR pathway seems to be a master regulator of cell physiology and may be a key player in the targeted therapy of cancer[87]. When the natural product rapamycin was discovered in the early 1970’s as an antifungal agent, it emerged in later studies that the molecule could halt growth in many types of eukaryotic cells and have a powerful immunosuppressive function.…”

Patient-derived xenograft (PDX) models in basic and translational breast cancer research

“…Unfortunately, in addition to significant urinary tract complications associated with the use of estradiol-containing implants of all sorts, the major issue with this approach is that the implant becomes depleted of hormone over time, requiring periodic replacement if hormone levels are to be maintained long-term. To address these issues, several groups have revisited use of an old method by testing the ability of estradiol-supplemented drinking water for its ability to support PDX growth with promising results (Table 3) (see [68,165–168,136] Lewis et al, unpublished). Given the significant limitations of delivery using implants, estradiol-supplemented drinking water may be a superior method of delivery.…”