Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor

Abstract

Summary The feasibility of performing broad and deep tumour genome sequencing has shed new light into tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones1,2. To add an additional layer of complexity, tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion as it occurs in infectious diseases. Here, we have studied the tumour genomic evolution in a patient with metastatic breast cancer bearing an activating PIK3CA mutation. The patient was treated with the PI3Kα inhibitor BYL719 and achieved a lasting clinical response, although eventually progressed to treatment and died shortly thereafter. A rapid autopsy was performed and a total of 14 metastatic sites were collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN, and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. Acquired bi-allelic loss of PTEN was found in one additional patient treated with BYL719 whereas in two patients PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To functionally characterize our findings, inducible PTEN knockdown in sensitive cells resulted in resistance to BYL719, while simultaneous PI3Kp110β blockade reverted this resistance phenotype, both in cell lines and in PTEN-null xenografts derived from our patient. We conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN- null phenotype resistant to PI3Kα inhibition.

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…One patient acquired a codon 12 KRAS, codon 61 KRAS and a codon 61 NRAS mutation together with a BRAF codon 600 mutation following acquired resistance to EGFR monoclonal antibody therapy that were not detectable prior to therapy (Bettegowda et al, 2014). Following acquired resistance to a PI3K alpha inhibitor, Juric and colleagues found parallel evolution of 6 distinct PTEN aberrations across 10 metastatic sites on the background of a clonal single copy PTEN deletion, reminiscent of second hit tumor suppressor gene loss following an early clonal event witnessed in breast and renal cancers (Juric et al, 2015).…”

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

“…5). In all, we assessed four treatment arms using agents targeting oncogenic HER2/neu (Lapatinib), PI3K/Akt signaling (α-Akt: MK-2206; α-pan-PI3K: NVP-BKM120), or Mek/Erk activity (α-Mek: GSK1120212) at doses routinely used in preclinical studies (15,29,31,32). Drug efficacy against the mouse protein target was verified by assessing the impact on signaling in treated tumor protein extracts (Fig.…”

“…For example, PTEN inactivation often arises in oncogenic receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2/ neu) amplified tumors in patients who acquire resistance to the HER2/neu targeting agent trastuzumab (10)(11)(12)(13)(14). Similarly, PTEN mutations were recently reported in a patient harboring PIK3CA mutations that developed resistance to the PI3Kα inhibitor BYL719 (15). Thus, PTEN inactivation occurs in advanced disease in patients with poor prognosis, defining a breast cancer subtype for which there is an unmet clinical need.…”

PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers

“…Moreover, clinical resistance to BYL719 in a metastatic breast cancer lesion carrying an activating PIK3CA mutation was attributed to loss of PTEN in this specific lesion (42). More recently, there have been reports that PI3K isoform usage in the context of PTEN loss is dependent on the genetic context by which the PI3K pathway is activated.…”