Table 3.

Mechanisms of resistance to HER2-targeted therapies.

Resistance-Causing Factor	Mechanism of Resistance	Strategies to Overcome Resistance	Resource
HER2(L755S) mutation	Activating mutation	Second-generation TKIs (neratinib)	[144,148]
Overexpression of HER1 and HER3	Enhancing the affinity of HER2/HER3 and HER1/HER3 and reducing HER2 binding to neratinib	Combined anti-HER2, PI3K inhibition and TKIs (neratinib and lapatinib)	[144,146,148,149]
Generation of p95HER2	A truncated form of HER2 that lacks the ECD but retains kinase activity	Combined chemotherapy (paclitaxel), trastuzumab and TKIs (lapatinib)	[144,148]
Overexpression of mucin 4 (MUC4) and the CD44–hyaluronan polymer complex	Masking the HER2 epitope as well as stabilizing and activating HER2	Combined soluble TNF inhibitors, trastuzumab and TKIs (lapatinib)	[144,146,148,149]
Loss of PTEN	Hyperactivation of the mTOR pathway	Combined PI3K trastuzumab and pertuzumab Combination of PI3K and MEK inhibitors	[144,145,146,148,149]
PIK3CA mutations	Increased and unregulated activation of the PI3K pathway	T-DM1 PI3K inhibitors in combination with trastuzumab and pertuzumab Combined mTOR inhibitor (everolimus), trastuzumab and chemotherapy	[144,145,146,148,149]
Expression of estrogen receptors	Offering an escape from HER2 signaling inhibition insuring tumor survival	Concomitant inhibition of both ER and HER2 signaling	[144,148]
Overexpression of Cyclin D1 and/or CDK4/6	Activating cell proliferation	Combination blocking of HER2 and ER and CDK4/6–cyclin D1 activation	[148,149]
RAS–MAPK activating mutations	Sustained activation of RAS–MAPK signaling	MEK–ERK inhibitors	[148]
Heterogeneous expression of HER2	Subclone lacking the target could escape the effects of the targeted therapy and lead to tumor recurrence	Potent HER2-targeted agents (T-DXd)	[144,148,150]
Expressing high levels of HLA g by tumor cells	Inhibiting NK cells through the engagement of killer cell immunoglobulin-like receptors (KIRs)	Combined blockade of HLA g and PDL1/PD1	[148]
Overexpression of CD47 by tumor cells	Inhibiting phagocytosis	Combination of magrolimab (mAb that targets CD47) and trastuzumab	[148]
Expression of CDK12- or RAC1 by tumor cells	Activating cell proliferation	Combinations of HER2 TKIs, CDK12 and RAC1 inhibitors	[148]
Increased activity and expression of the drug efflux pump	Reducing the cytotoxic effect of T-DM1	Combination of T-DM1 and pump inhibitors	[144]
c-MET hyperactivity or amplification	Inducing HER3-mediated activation of PI3K Sustained Akt activation	c-MET inhibitors	[145,146,149]
Overexpression of IGF1R	Activation of HER2 Inducing degradation of p27	IGF1R signaling inhibition	[145,146]
Src activation	Inhibiting PTEN	Combination of trastuzumab and Src inhibitor (dasatinib)	[145,149]
Suppression of the PP2A family	Sustained activation of the PI3K/AKT/mTOR pathway	Combination of EZH2 inhibitor with HER2-targeted therapy	[145]
Upregulation of miR-221	Inhibiting PTEN Targeting p57 and p27	Src inhibitors	[145]
AXL overexpression	Activation of PI3K/AKT and MAPK pathways in a ligand-independent manner	AXL inhibitor plus trastuzumab	[151]
Upregulation of MCL-1	Inhibition of apoptosis	PARP inhibitor (olaparib)	[149,152]
Co-expression of HER2(T862A) and HER2(L755S) mutations	Enhancing HER2 activation and impairing TKIs sensitivity	Combined inhibition of HER2 and MEK	[153]
Activating mutations in TGF-β	Enhancing HER ligand shedding	Trastuzumab, pertuzumab and TGFꞵ inhibitors	[146,149]