Molecular Mechanisms and Therapeutic Strategies to Overcome Resistance to Endocrine Therapy and CDK4/6 Inhibitors in Advanced ER+/HER2- Breast Cancer

Abstract

Approximately 70-80% of breast cancers are estrogen receptor-positive (ER+), with 65% of these cases also being progesterone receptor-positive (ER+PR+). In most cases of ER+ advanced breast cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These include tamoxifen, a selective estrogen receptor modulator (SERM); fulvestrant, a selective estrogen receptor degrader (SERD); and aromatase inhibitors (AIs), which block estrogen synthesis. However, intrinsic or acquired hormone resistance eventually develops, leading to disease progression. The combination of ET with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) has been shown to significantly increase progression-free survival (PFS) and, in some cases, overall survival (OS). CDK4/6is works by arresting the cell cycle in the G1 phase, preventing DNA synthesis, and enhancing the efficacy of ET. This review highlights the key mechanisms of resistance to ET, whether used alone or in combination with biological agents, as well as emerging therapeutic strategies aimed at overcoming resistance. Addressing ET resistance remains a work in progress, and in the near future, better patient selection for different therapeutic approaches is expected through the identification of more precise biological and genetic markers. In particular, liquid biopsy may provide a real-time portrait of the disease, offering insights into mechanisms driving ET resistance and cancer progression.

Keywords: CDK4/6 inhibitors; advanced ER+/HER2− breast cancer; endocrine resistance; endocrine therapy.

Figure 1

(A) Complexity of the molecular pathways governing the function of the cyclin-dependent kinases (CDKs) through the cell-division cycle. (B) Key mechanisms of CDK7 and CDK7 inhibition in ER+ breast cancer cells. The cell-division cycle starts depending on the tangled interplay of CDK4 and CDK6 complexes, which involve D-type cyclins and the release of E2F transcription factors by pRb phosphorylation. They regulate the transcription of genes that play a key role in S-phase advance. S-phase progression is then regulated by the cooperation of CDK2-cyclin E/cyclin A complexes. CDK function arrangement is promoted by CDKis, particularly in addressing CDK4/6 or CDK2. Progression from the G2 phase to the M phase is governed by the collaborating A and B cyclins along with CDK1. CDK: cyclin-dependent kinase; p: protein; Rb: retinoblastoma; P: phosphorylation; CDK7i: cyclin-dependent kinase 7 inhibition; E2F: early region 2 binding factor; TP53: tumor protein p53. Also, see the text.

Figure 2

The main mechanisms of resistance to ET and/or CDK4/6is in advanced ER+/HER2− breast cancer. (a) These include ERBB2, FGFR1/2, EGFR, IGFR1, and NOTCH; (b) in Akt1, PI3KCA, PTEN, HRAS, KRAS, and NRAS; (c) ESR1 Y537S/Y537N mutations; RTK: receptor tyrosine kinase; PI3K: phosphoinositide 3 kinase; PTEN: phosphatase and tensin homolog; Akt: protein kinase B; mTOR: mammalian target of rapamycin; EGFR: epidermal growth factor receptor; ERBB2: receptor tyrosine-protein kinase erbB2; FGFR1/2: fibriblast growth factor receptor 1/2; IGFR1: insulin-like growth factor receptor 1; NOTCH: notch signaling pathway; MAPK: mitogen-activated protein kinase; Rb: retinoblastoma; RAS: rat sarcoma virus protein superfamily; NF1: neurofibromatosis type 1 gene; RAF: rapidly accelerated fibrosarcoma protein kinase; MEK: mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase; FAT1: protein encoded by FAT gene that takes part of the cadherin superfamily proteins; MST1/2: macrophage-stimulating protein 1/2; LATS1/2: large tumor suppressor kinase 1/2; YAP: yes-associated protein-1; TAZ: transcriptional adaptor putative zinc finger; TEAD: TEA domain family member; CDK: cyclin-dependent kinase; p: protein; SMAD4: smad family member 4; PMM2 m.r.; phosphomannomutase 2 metabolic reprogramming; APOBEC3 g.a.: apolipoprotein B mRNA-editing enzyme, catalytic subunit 3, genetic alteration; PKMYT: membrane-associated tyrosine and threonine specific cdc 2-inhibitory kinase; MYSM1: Myblike, SWIRM and MNP domain 1; MNX1: motor neuron and pancreas homeobox 1; ACC1 m.r.: acetyl-CoA carboxylase 1 metabolic reprogramming; CYP19A1: member of the cytochrome P450 superfamily; MLL3 g.a.: myeloid lymphoid or mixed lineage leukemia protein 3 genetic alterations; COLL11A1: collagen, type XI, alpha 1; BCAR4: breast cancer anti-estrogen resistance protein 4; RFC3: replication factor C subunit 3; AEs: anti-estrogens; ERalpha: estrogen receptor alpha; ERE: estrogen receptor element; TATA: tiamine-adenine sequence; c-myc: family of genes overexpressed in various cancers and homologous with an avian virus; circHIAT1: circular RNA HIAT1; miR-19a-3p: microRNA 19a-3p; CADM2: cell adhesion molecule 2; NF-κB: nuclear factor kappa-light chain enhancer of activated B cells; AP-1: activating protein-1; E2F: transcription factor E2F; t.f.: franscription factor; HDAC: hystone deacetylase; LncRNA: long non-coding RNA; AURKA: aurora kinase A; CCNE1/2: genes encoding cyclin E1/E2 proteins; DNMT1: DNA methyltransferase 1; DDR: DNA damage repair; BRCA1/2: breast cancer type 1/2 genes; HRR: homologous recombination repair; HRD: homologous repair deficiency; TP53: tumor protein 53; DDCKPS: DNA damage checkpoints signaling; ATM: part of serine/threonine protein kinase ATM; ATR: ataxia-teleangectasia and RAD3 related; CHEK2: checkpoint kinase 2; PD-L1: programmed death ligand 1; TILs: tumor-infiltrating lymphocytes; IRPS: interferon-related palbociclib-resistance signature; IL: interleukin; P: phosphorylation. increase. Decrease. (Also see text).

Figure 3

Progression-free survival correlated to hormonal therapy (survival median time of HIT 33.1 (95% CI 24.5–41.8); survival median time of HT 18 (95% CI 12.1–23.8)). HIT: hormone immunotherapy; HT: hormone therapy. Reproduced with permission by Nicolini A., et al. J. Cancer Metastasis Treat. 2022 8, 13 [190].