High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

Abstract

CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.

Hypoxia and ERα Transcriptional Crosstalk Is Associated with Endocrine Resistance in Breast Cancer

“…Therapy resistance remains a clinical challenge and there is a critical need to identify etiological factors accounting for such phenomenon in each of the different breast cancer subtypes [36][37][38]. While different cancer cell-intrinsic mechanisms have been proposed to favor endocrine resistance, ranging from gene amplification [39], parallel growth factor signaling [40,41], phenotypic plasticity [42] to epigenetic [43,44] and metabolic reprogramming [45], very little is known about the contribution of the tumor microenvironment (TME).…”

CDK4/6 inhibitor resistance in estrogen receptor positive breast cancer, a 2023 perspective

“…However, endogenous CDK inhibitors can hinder the action of synthetic CDK4/6 inhibitors. In ER + breast cancer, overexpression of p16 has been associated with CDK4/6 inhibitor resistance and poor clinical outcome ( Palafox et al, 2022 ). In addition, p18 binds to the CDK6-CycD complex blocking the therapeutic action of CDK4/6 inhibitors (palbociclib or abemaciclib), and conversely CDK4/6 inhibitor sensitivity is restored by suppressing the binding of p18 to CDK6 ( Li et al, 2022 ).…”

“…The low occurrence of RB1 mutation prior to use of CDK4/6 inhibitors compares with an incidence of 2%–9% in patients at the time of progression on CDK4/6 inhibitor therapy, suggesting that it is more commonly an acquired mechanism of resistance ( Asghar et al, 2022 ). Loss of heterozygosity (LOH) of RB1 is also significantly associated with intrinsic CDK4/6 inhibitor resistance, and RB1 mutation is frequently acquired in CDK4/6 inhibitor treated patients and pre-clinical models with pre-existing RB1 LOH ( Palafox et al, 2022 ; Safonov et al, 2022 ).…”

“…There are however discordant results clinically. Higher levels of CCNE1 mRNA were detected in resistant compared to sensitive tumors in the abemaciclib ABC-POP ( Palafox et al, 2022 ) and palbociclib PALOMA-3 trials ( Turner et al, 2019 ), whereas altered CCNE1 expression was not significantly associated with an altered response to palbociclib plus letrozole in the PALOMA-2 trial ( Finn et al, 2020 ).…”

Biomarkers of Response and Resistance to CDK4/6 Inhibitors in Breast Cancer: Hints from Liquid Biopsy and microRNA Exploration

“…Increased expression of the cyclin-dependent kinase inhibitors 2D (CDKN2D, p19) and 2C (CDKN2C, p18), which belong to the INK4 family, has also been associated with reduced efficacy of CDK4/6 inhibitors plus ET [ 19 , 20 ], suggesting that these tumors may have already lost their dependency on the CDK4/6 restriction point. In addition, upregulation of p16 (CDKN2A) at the protein level [ 24 ] and an increase in the expression of E2F targets and other cell-cycle-related pathways, including Myc regulation [ 19 ], has been reported in patients with resistant BC, highlighting the critical role of these genes in the clinical efficacy of CDK4/6 [ 19 , 20 ].…”