SINGLE-TARGET INHIBITION OF THE PI3K/AKT/mTOR (PAM) PATHWAY LEAVES OPENINGS FOR HR+/HER2- ADVANCED/METASTATIC BREAST CANCER TO BREAK THROUGH1-4

Comprehensive inhibition of the PAM pathway is needed to overcome the limitations of current single-target inhibitors2,3,5,6

PAM PATHWAY

The PI3K/AKT/mTOR (PAM) pathway is a cancer control center

The PAM pathway is a driver of HR+/HER2- advanced/metastatic breast cancer, contributing to key cellular processes involved in oncogenesis and tumor progression3,7-13

Cell metabolism
Cell survival
Cell proliferation

PAM pathway hyperactivation can be an oncogenic process independent of PIK3CA mutational status.3,11,14

PATHWAY CROSSTALK

PI3K/AKT/mTOR (PAM) pathway crosstalk allows for adaptive resistance that maintains pathway viability1,2,4,6,11,12,15,16

The multiple components of the PAM pathway provide functional redundancy via feedback loops that limit the activity of single-target PAM pathway inhibitors.1,2,4,6

Single-target inhibition
Inhibition arrow
Adaptive resistance
PI3K-α
inhibition
  • PI3K-β signaling enhanced17-19
  • mTORC1 signaling enhanced20-22
AKT
inhibition
  • mTORC1 signaling enhanced23,24
  • RTKs are upregulated25
mTORC1
inhibition
  • PI3K-AKT signaling enhanced26-28
  • RTKs are upregulated27
PI3K/AKT/mTOR (PAM) pathway crosstalk allows for adaptive resistance that maintains pathway viability

Single-target PAM pathway inhibition allows tumors to develop escape mechanisms.

Multi-target, comprehensive PAM pathway inhibition is needed.2,3,5,6,30

Figure adapted from Glaviano A, et al. Mol Cancer. 2023;22(1):138; He Y, et al. Sig Transduct Target Ther. 2021; 425(6):1-17; Hoxhaj G, et al. Nat Rev Cancer. 2020;20(2):74-88; Manning BD, et al. Cell. 2017;169(3):381-405.
CURRENT CHALLENGES
For patients with HR+/HER2- advanced/metastatic breast cancer who have progressed on endocrine-based therapy,

Current single-target inhibitors of the PI3K/AKT/mTOR (PAM) pathway fall short31-34

Many targeted therapies may offer:

Limited eligibility

Predominantly indicated for those with PIK3CA/AKT1 mutations, excluding most patients31-35

Modest efficacy

Provide modest mPFS benefit in the second-line setting31-34

Tolerability challenges

Associated with adverse events such as hyperglycemia, rash, and diarrhea, which often lead to dose interruptions, dose reductions, and discontinuations31-34

There is a need for a comprehensive PAM inhibitor that is efficacious, tolerable, and demonstrates activity in a broad population of patients, independent of PIK3CA mutational status.3,6,36

PAM-ER-CDK4/6

The PI3K/AKT/mTOR (PAM) pathway can drive treatment resistance to both ER- and CDK4/6-based treatments37-43

Interaction between estrogen, cyclin D1-CDK4/6, and PAM signaling pathways increases the complexity of therapeutic targeting in HR+/HER2- advanced/metastatic breast cancer.37,44,45

Estrogen, cyclin D1-CDK4/6, and PI3K/AKT/mTOR (PAM) signaling pathways interact in HR+/HER2- advanced/metastatic breast cancer

The PAM pathway can induce estrogen-dependent and estrogen-independent ER activity46-48

ER can directly activate PI3K, fueling PAM pathway activity49

The PAM and ER pathways can induce cyclin D1 upregulation, driving activation of the cyclin D1-CDK4/6 pathway50-52

PAM POTENTIAL

Comprehensive inhibition of the PI3K/AKT/mTOR (PAM) pathway may present a new path forward in treatment

Blocking the PAM pathway comprehensively may overcome treatment resistance and enhance sensitivity to ER- and CDK4/6-based treatments, offering additional options for patients with HR+/HER2- advanced/metastatic breast cancer who have experienced disease progression.6,37,53-60

An image of a dam with 3 closed doors, stopping water from flowing through

Celcuity is closing in on the potential of comprehensive PAM pathway inhibition

Learn more about Celcuity

AKT=protein kinase B; AKT1=protein kinase B subunit 1; CDK4/6=cyclin-dependent kinases 4 and 6; ER=estrogen receptor; HER2-=human epidermal growth factor receptor 2 negative; HR+=hormone receptor positive; mPFS=median progression-free survival; mTOR=mammalian target of rapamycin; mTORC1=mammalian target of rapamycin complex 1; mTORC2=mammalian target of rapamycin complex 2; PI3K=phosphoinositide 3-kinase; PI3Kα=PI3K subunit alpha; PI3Kβ=PI3K subunit beta; PIK3CA=phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

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