Cracking the challenge of resistance to HER2-targeted therapy in breast cancer

HER2-positive breast cancer accounts for approximately 15% of all breast cancers. Although anti-HER2 targeted therapies have dramatically improved patient survival, primary and acquired resistance remain major clinical challenges. A comprehensive review recently published by researchers from Fudan University Shanghai Cancer Center, Kunming Medical University, and several collaborating institutions—“HER2-targeted therapy resistance in breast cancer: from molecular landscape to clinical aspects”—systematically maps the molecular landscape of resistance to HER2-directed therapy, strategies to overcome it, and tools for predicting treatment efficacy, providing an important reference for the future of precision medicine.

 

HER2 biology and the evolution of targeted therapy

HER2 (ERBB2) is a member of the HER receptor family; its amplification or overexpression drives sustained activation of the downstream PI3K-AKT and MAPK pathways and, with it, tumor proliferation. Drug development against this target has evolved from first-generation monoclonal antibodies such as trastuzumab, through tyrosine kinase inhibitors (TKIs), to today’s era of antibody-drug conjugates (ADCs). Tumor cells, however, can “escape” therapeutic pressure through multiple mechanisms, leading to resistance.

 

A panoramic view of resistance mechanisms

The review details ten major categories of resistance mechanisms:

•ERBB family mutations and compensation. Activating mutations such as HER2 L755S can mediate resistance to lapatinib and T-DM1, though irreversible TKIs such as neratinib remain effective; HER3 mutations or overexpression sustain PI3K signaling and drive resistance.

•Crosstalk with other receptor tyrosine kinases. IGF-1R, EphA2, c-MET, and SRC form heterodimers with HER2 and reactivate pro-survival pathways.

•Loss or masking of the HER2 extracellular domain. Truncated forms such as p95HER2 lack the antibody-binding site, while glycoproteins such as MUC4 sterically mask the epitope, leaving trastuzumab with “no target to hit.”

•Compensatory activation of downstream pathways. Persistent PI3K-AKT or MAPK/ERK signaling—often accompanied by PIK3CA mutations or PTEN loss—is a core driver of resistance and can be reversed by combining PI3K or CDK4/6 inhibitors.

•Immunosuppressive tumor microenvironment. The neurotransmitter neuromedin U (NmU), the immune checkpoint CMTM6, and cancer-associated fibroblasts (CAFs)

weaken antibody-dependent cellular cytotoxicity (ADCC).

•HER2 heterogeneity. Uneven HER2 expression or gene amplification within tumors allows subpopulations of cells to escape targeted killing—an important cause of resistance to T-DM1.

•ADC-specific resistance. Mechanisms include upregulated DNA damage repair, EGFR overexpression that competes for internalization, loss of immunogenic cell death (ICD), and p95HER2-mediated immunosuppression.

•HER2–ER signaling crosstalk. Patients with hormone receptor-positive disease often respond less well, pointing to crosstalk between the endocrine and HER2 pathways.

•The brain metastasis microenvironment. The blood-brain barrier and components such as AXL and the extracellular matrix (ECM) within brain lesions promote local resistance.

•Metabolic reprogramming. Altered fatty acid oxidation, glutamine utilization, and cysteine metabolism help tumor cells survive under therapeutic pressure.

 

Clinical strategies and predictive tools to overcome resistance

Multiple combination strategies have been tested in the clinic to counter these mechanisms:

•Dual HER2 blockade. Trastuzumab plus pertuzumab blocks HER2 homo- and heterodimerization in a complementary manner.

•Brain penetration by TKIs. Tucatinib, pyrotinib, and related agents have shown remarkable efficacy against HER2-positive brain metastases.

•Next-generation ADCs. T-DXd (trastuzumab deruxtecan), with its high drug-to-antibody ratio (DAR=8) and potent bystander effect, has redefined the standard of care in HER2-positive, HER2-low, and even HER2-ultralow disease. The DESTINY-Breast program of clinical trials demonstrated a median progression-free survival (PFS) of 40.7 months for first-line T-DXd plus pertuzumab, a substantial improvement over the conventional THP regimen. The domestically developed third-generation ADC SHR-A1811 has likewise shown an excellent pathological complete response (pCR) rate with manageable pulmonary toxicity.

•Overcoming ADC resistance. Against p95HER2, neratinib can promote its degradation and restore immune responses; against EGFR interference, combining EGFR inhibitors can increase T-DXd internalization.

 

Therapeutic prediction tools. On the predictive side, the PAM50 subtype classification, tumor-infiltrating lymphocytes (TILs), the HER2DX model, and artificial intelligence–based imaging analysis are helping to identify the patients most likely to benefit, paving the way for chemo-sparing and de-escalated treatment.

 

Conclusions and future perspectives

The review emphasizes that despite the tremendous success of ADCs, resistance and toxicities—such as interstitial lung disease—remain unmet clinical needs. Future research should focus on:

• Elucidating the complex mechanisms of ADC resistance and developing combination strategies;

• Leveraging multi-omics technologies to realize truly individualized treatment;

• Exploring synergies between metabolic intervention, immunotherapy, and anti-HER2 therapy.

 

As an expanding arsenal of precision tools emerges, the management of HER2-positive breast cancer is moving toward “whole-domain” care—including HER2-low disease and brain metastases—with the ultimate goal of turning drug resistance into a preventable and controllable chronic condition.

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