Precision therapy for driver gene mutations in breast cancer: Current landscape and future perspectives

Table 2 Acquired resistance mechanisms and subsequent management strategies for major targeted therapies in breast cancer

Prior therapy	Category of resistance mechanism	Specific molecular event	Biological consequence	Potential subsequent strategy	Clinical evidence/considerations	Validation level
CDK4/6 inhibitors (e.g., palbociclib)	Cell cycle pathway alteration	RB1 gene loss/mutation	Loss of key downstream brake, uncontrolled cell cycle	Switch to chemotherapy; ADCs (e.g., sacituzumab govitecan)	Poor prognosis, reduced response to subsequent endocrine therapy[18]	Clinically validated
CDK4/6 inhibitors (e.g., palbociclib)	Upstream pathway activation	Acquired PIK3CA or AKT1 mutations	Activation of alternative pathways, bypassing G1 arrest	Combine with or switch to pathway inhibitors (e.g., alpelisib, capivasertib)	SOLAR-1, CAPItello-291 studies show PFS benefit[5,9]	Clinically validated
CDK4/6 inhibitors (e.g., palbociclib)	Other mechanisms	Cyclin E (CCNE1/2) amplification; CDK2 upregulation	Direct drive into S phase, independent of CDK4/6	Investigational CDK2 inhibitors; novel SERDs	Clear preclinical evidence, clinical trials ongoing[19]	Emerging clinical/preclinical
PI3Kα inhibitor (e.g., alpelisib)	Target up/downstream alteration	PTEN loss; AKT1 E17K mutation	Enhanced pathway signaling output	Switch to AKT inhibitor (capivasertib)	CAPItello-291 study confirms capivasertib efficacy[9]	Clinically validated
PI3Kα inhibitor (e.g., alpelisib)	Bypass activation	ERBB2/HER2, FGFR, MET amplification/overexpression	Reactivation of downstream signaling via RTKs	Corresponding RTK inhibitors (e.g., neratinib) in combination	Requires identification via NGS; mostly in trials[20]	Emerging clinical/preclinical
PARP inhibitor (e.g., olaparib)	HRR function restoration	BRCA1/2 reversion mutations	Restores HRR, abolishes “synthetic lethality”	Switch to platinum-based chemotherapy; DNA damaging agents	Common cross-resistance with platinum; clinical evidence[21]	Clinically validated
Selective ER degrader (e.g., elacestrant)	Continued ER activation	De novo or clonally expanded ESR1 mutations (e.g., Y537S)	Insensitivity to existing SERDs, constitutive activation	Switch to chemotherapy; explore next-gen SERDs or PROTACs	Different ESR1 mutations have varying SERD sensitivity[24]	Clinically validated
Selective ER degrader (e.g., elacestrant)	Bypass pathway activation	PIK3CA, AKT1 mutations	Provides ER-independent growth signals	Combine with PI3K/AKT/mTOR pathway inhibitors	A common mechanism for endocrine therapy resistance[26]	Emerging clinical

CDK4/6: Cyclin-dependent kinase 4/6; ADC: Antibody-drug conjugate; HRR: Homologous recombination repair; PROTAC: Proteolysis targeting chimera; RTK: Receptor tyrosine kinase; SERD: Selective estrogen receptor degrader; PFS: Progression-free survival; NGS: Next-generation sequencing; ER: Estrogen receptor; PARP: Poly ADP-ribose polymerase; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin.