PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer

Abstract

The combination of CDK4/6 inhibitors with antiestrogen therapies signifi cantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN , through increased AKT activation, was suffi cient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these fi ndings provide critical insight into how this single genetic event may cause clinical crossresistance to multiple targeted therapies in the same patient, with implications for optimal treatmentsequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as fi rst-line treatment for ER-positive advanced breast cancer. Importantly, these fi ndings have near-term clinical relevance because PTEN loss also limits the effi cacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.

MAST1 modulates neuronal differentiation and cell cycle exit via P27 in neuroblastoma cells

“…The mechanism by which MAST1 regulates P27 expression is not clear and needs further investigation. A previous study showed that MAST1 stabilized PTEN [36] and that PTEN increases the levels of P27 [37]. Taken together, these observations support our speculation that P27 may function downstream of MAST1.…”

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients withAKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer

“…Indeed, in SOLAR-1, the small subset of patients with prior CDK4/6 inhibitor exposure did still appear to derive benefit from the addition of apelisib to fulvestrant (17). Additionally, of interest, recent preclinical data have implicated PTEN loss, as a potential mechanism of resistance to CDK4/6 inhibitors, via increased AKT activation in vitro and in vivo (53), a hypothesis since observed in the clinic where enrichment of PTEN loss-of-function alterations has been described in tumor samples obtained after CDK4/6 inhibitor therapy (54). Intriguingly, in this context (PTEN-null models resistant to CDK4/6 inhibitors), AKT inhibition may in fact be superior to PI3K inhibition (53).…”

“…Additionally, of interest, recent preclinical data have implicated PTEN loss, as a potential mechanism of resistance to CDK4/6 inhibitors, via increased AKT activation in vitro and in vivo (53), a hypothesis since observed in the clinic where enrichment of PTEN loss-of-function alterations has been described in tumor samples obtained after CDK4/6 inhibitor therapy (54). Intriguingly, in this context (PTEN-null models resistant to CDK4/6 inhibitors), AKT inhibition may in fact be superior to PI3K inhibition (53). It is also clear from preclinical work that constitutively active AKT induces resistance to PI3K inhibition in breast cancer cell lines, and, interestingly, increased AKT1 expression was identified in a very small cohort of biopsies collected post-treatment with alpelisib (55).…”

The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer

“…16 Despite lack of robust data supporting a role for PI3K, loss of the PTEN tumor suppressor was recently noted in tumor samples with progression on ribociclib, and was sufficient to promote resistance in vitro . 17 Preclinically, PDK1, another PI3K pathway effector, emerged from a kinome-wide screen in HR+ cells as a potential mediator of resistance to CDK4/6i; targeting PDK1 or PI3K prompted resensitization to CDK4/6i. 18…”