and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling

Human breast cancers that have HER2 amplification/overexpression frequently carry PIK3CA mutations, and are often associated with a worse prognosis. However, the role of PIK3CA mutations in the initiation and maintenance of these breast cancers remains elusive. In the present study, we generated a compound mouse model that genetically mimics HER2-positive breast cancer with coexisting [PIK3CA.sup.H1047R]. Induction of [PIK3CA.sup.H1047R] expression in mouse mammary glands with constitutive expression of activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. Interestingly, inducible expression of mutant PIK3CA resulted in a robust activation of phosphatidylinositol-3-kinase (PI3K)/AKT signaling but attenuation of Her2/Her3 signaling, and this can be reversed by deinduction of [PIK3CA.sup.H1047R] expression. Strikingly, although these [Her2.sup.+] [PIK3CA.sup.H1047R]initiated primary mammary tumors are refractory to HER2-targeted therapy, all tumors responded to inactivation of the oncogenic [PIK3CA.sup.H1047R], a situation closely mimicking the use of a highly effective inhibitor specifically targeting the mutant PIK3CA/p110α. Notably, these tumors eventually resumed growth, and a fraction of them escaped PI3K dependence by compensatory ERK activation, which can be blocked by combined inhibition of Her2 and MEK. Together, these results suggest that PIK3CA-specific inhibition as a monotherapy followed by combination therapy targeting MAPK and HER2 in a timely manner may be an effective treatment approach against HER2-positive cancers with coexisting PIK3CA- activating mutations. Oncogene (2016) 35, 2961-2970; doi:10.1038/Onc.2015.377;published online 7 December 2015