PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer

Abstract

There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation.

MET and ERBB2 Are Coexpressed in ERBB2+ Breast Cancer and Contribute to Innate Resistance

“…6B). This supports the observations of Serra and colleagues where PI3K inhibition in ERBB2-overexpressing cells was compensated for by ERK/MAPK dependence (30). We also examined other kinases downstream of the MET and ERBB2 receptors using a phospho-kinase antibody array of 42 kinases, but observed no differences in their activity.…”

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

“…This model also revealed that the lack of R-Ras2 promotes signalling compensation mechanisms in tumours similar to those seen before on the inactivation of specific PI3K/mTORC route signalling elements [39][40][41][42][43][44][45] . In those cases, such compensation effects are mostly mediated by the elimination of mTORCdependent negative feedbacks on the Raf/Erk route [39][40][41][42][43][44][45] . However, the development of these signatures in MMTVHer2 tg ;Rras2 À / À mice seems to require long-term Darwinian selection events, because primary MECs from both MMTVHer2 tg ;Rras2 À / À (this work) and Rras2 À / À knockout mice 18 do not exhibit such signatures.…”

“…Despite this, the R-Ras2-dependent PI3Ka pool is clearly relevant in vivo, given the marked tumorigenic and metastatic defects shown by R-Ras2-deficient breast cancer cells when implanted in recipient mice. The morphogenetic alterations seen in preneoplasic mammary glands of MMTV-Her2 tg ;Rras2 À / À mice, together with the signalling compensation events detected in tumours arising in those mice, are also indirect evidence in favour of defects in the PI3Ka/Akt/ mTORC route in this experimental model 30,31,[39][40][41][42][43][44][45] . However, as reconstitution experiments are not possible in this case, we cannot formally exclude the possibility that those events could be generated by defects in other R-Ras2-dependent signalling routes (Supplementary Discussion).…”

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

“…These gain-of-function mutations in the PI3KCA gene are found in a broad range of cancers, and they are highly enriched in breast cancer, where they are observed in 20-25% of cases (7). In addition, breast cancers with amplified HER2, which comprise ∼20% of all breast cancers, (8) are also particularly sensitive to PI3K inhibition (9)(10)(11). However, even among patients whose cancers harbor PIK3CA mutations, a significant heterogeneity of responses has been observed to PI3K inhibitors currently being tested in clinical studies (3)(4)(5).…”