Overcoming Therapeutic Resistance of Triple Positive Breast Cancer with CDK4/6 Inhibition

Table 3

Potential pathways of resistance to antihormonal agents, HER2 inhibitors and CDK4/6 inhibitors.

Mechanisms	Resistance to therapy	Counteracted by
Cell cycle checkpoints pathway
Cyclin D1 amplification or overexpression	Endocrine therapy (P, C)^a [35, 36]	CDK4/6 inhibitors [37–40]
CDK4 amplification	CDK4/6 inhibitors (P) [41, 42]	To be studied
CDK6 amplification	CDK4/6 inhibitors (P)^b [43]	To be studied
Cyclin E1 amplification or overexpression	Endocrine therapy (P, C) [44]; HER2 inhibitors (P, C) [45]; CDK4/6 inhibitors (P) [46]	CDK2 inhibitors [45]
Cyclin E2 amplification or overexpression	Endocrine therapy (P) [47]	CDK2 inhibitors [47]
RB loss	CDK4/6 inhibitors (P) [37, 48]	To be studied
p21 loss	Endocrine therapy (P, C) [49, 50]; CDK4/6 inhibitors (P) [51]	To be studied
p27 loss	Endocrine therapy (P, C) [50, 52]; CDK4/6 inhibitors (P) [51]	To be studied
ESR1 activating mutations	Endocrine therapy (P, C) [53–55]	CDK4/6 inhibitors [56]; mTOR inhibitors [57]; Fulvestrant [56]; Novel ER antagonists [58]
MAPK kinase pathway
HER2 amplification	Endocrine therapy (P, C) [7, 20–28]	HER2 inhibitors [13, 59]
HER2 truncation (p95HER2) or mutations in the extracellular domain	HER2-targeted antibodies (P, C) [60, 61]	HER2 small molecule inhibitors [61]
HER3 amplification	HER2 inhibitors [62]	HER3 inhibitors [63–65]
C-MYC overexpression	Endocrine therapy (P) [66]	CDK1 inhibitors [67, 68]
PI3K/AKT/mTOR pathway
PI3K pathway activation	Endocrine therapy (P, C) [69]; HER2 inhibitors (P) [62, 70, 71]	PI3K inhibitors [72]; mTOR inhibitors [62, 71, 73]; CDK4/6 inhibitors [74]

a–P: resistance demonstrated in preclinical studies; C: resistance shown in clinical studies; b: amplification of CDK6 has been linked to both sensitivity [41] and resistance [43] to CDK4/6 inhibitors; additional studies are needed.