The cyclin D1–CDK4/6–Rb axis is a central regulator of the G1-to-S phase cell cycle transition and is hyperactivated in the majority of HR+ breast cancers. CDK4/6 inhibitors block Rb phosphorylation, inducing G1 arrest and suppressing tumor proliferation. Three agents are now standard-of-care first-line treatments in combination with endocrine therapy for HR+/HER2− advanced breast cancer, with median PFS exceeding 24 months [1, 2]. Despite their efficacy, acquired resistance is nearly universal — driven by CDK2 upregulation, CCNE1 amplification, and RB1 loss [3].

Next-generation strategies include CDK2 and CDK7 inhibitors; samuraciclib (CT7001), a selective CDK7 inhibitor, demonstrated promising activity in the Phase 2 SUMIT-BC trial in combination with fulvestrant following CDK4/6i progression [4].

Activating mutations in PIK3CA occur in approximately 40% of HR+/HER2− metastatic breast cancers and represent a major driver of endocrine resistance. Three nodes of this pathway have been clinically validated: alpelisib (PI3Kα inhibitor) and capivasertib (AKT inhibitor) are both FDA-approved in combination with fulvestrant for PIK3CA/AKT/PTEN-altered endocrine-resistant disease [5], while everolimus (mTORC1 inhibitor) has long been used with exemestane.

Emerging agents include inavolisib, a mutant-selective PI3Kα inhibitor, and gedatolisib, a potent multi-node PI3K/mTOR inhibitor currently being evaluated in the Phase 3 VIKTORIA-2 trial in combination with CDK4/6 inhibitors and fulvestrant [6].

ESR1 mutations arise in 40–50% of patients following prolonged aromatase inhibitor therapy and confer ligand-independent ER activation, driving resistance to standard endocrine therapy. Oral SERDs have emerged as a critical therapeutic class to address this resistance.

Elacestrant, the first FDA-approved oral SERD, demonstrated superior PFS over standard endocrine therapy in ESR1-mutant metastatic breast cancer in the Phase 3 EMERALD trial [7]. Camizestrant, a next-generation oral SERD, showed a striking PFS benefit (16.0 vs. 9.2 months, HR 0.44) when switched early upon ctDNA-detected ESR1 mutation emergence during first-line CDK4/6i therapy in the SERENA-6 trial [8].

Four TKIs are currently approved: lapatinib (reversible EGFR/HER2 dual inhibitor), neratinib (irreversible pan-HER inhibitor, active in adjuvant and CNS settings), tucatinib (highly selective reversible HER2 inhibitor), and pyrotinib (irreversible pan-HER inhibitor, approved in China).

Tucatinib, in combination with trastuzumab and capecitabine, demonstrated significant OS benefit including in patients with active brain metastases in the HER2CLIMB trial, establishing it as a preferred option for CNS disease [10]. A Phase 2 basket study further demonstrated that tucatinib plus trastuzumab achieved a 41.9% ORR in HER2-mutated (non-amplified) metastatic breast cancer, expanding the potential patient population [11]. Network meta-analyses suggest pyrotinib/capecitabine and tucatinib/trastuzumab/capecitabine rank among the most efficacious TKI-containing regimens [12].

PARP inhibitors exploit synthetic lethality in tumors harboring germline BRCA1/2 mutations, which impair homologous recombination repair. Olaparib and talazoparib are approved for gBRCA-mutant metastatic TNBC, and combinations with immunotherapy are under active investigation [14].

PI3K/AKT pathway inhibitors, particularly capivasertib, are being evaluated in TNBC given frequent PTEN loss and PIK3CA mutations in this subtype. EGFR inhibitors have shown limited single-agent activity despite high EGFR expression in basal-like TNBC, though combinations with chemotherapy or other targeted agents continue to be explored. Androgen receptor (AR) antagonists such as enzalutamide and bicalutamide show activity in the LAR (luminal androgen receptor) molecular subtype of TNBC.

Emerging targets include the G2/M checkpoint kinases WEE1 and ATR, which are particularly relevant in TP53-mutant TNBC where G1 checkpoint loss creates dependency on the G2/M checkpoint for DNA damage repair [15]. The JAK2/STAT3 pathway, frequently activated in specific TNBC subtypes, is also under investigation with both small molecule inhibitors and PROTAC degraders [16].

PROTAC technology is gaining traction in TNBC. An MDM2-targeting PROTAC demonstrated potent apoptosis induction specifically in p53-inactivated TNBC cells and xenografts, exploiting an unexpected MDM2 dependency in this context [17]. A PRMT5-targeting PROTAC (YZ-836P) showed superior efficacy over existing PRMT5 inhibitors in TNBC patient-derived organoids and xenograft models [18].