Targeted Therapies Overcoming Endocrine Resistance in Hormone Receptor-Positive Breast Cancer

Abstract

Breast cancer is a heterogeneous disease with different molecular subtypes. Most tumours are hormone receptor positive (luminal subtype) with potential endocrine responsiveness. Endocrine therapy is commonly used in these patients. Disease progression caused by endocrine resistance represents a significant challenge in the treatment of breast cancer. To understand the mechanisms of resistance of long-term oestrogen-deprived breast cancer cells, it is important to focus on cross-talk between steroid receptor signalling and other growth factor receptors and intracellular pathways. (Pre-)clinical trials showed that co-targeting these pathways can restore endocrine sensitivity. The focus of the current review is on the intracellular PI3K/AKT/mTOR signalling pathway and cyclin-dependant kinases (CDKs) in oestrogen receptor (ER)-positive breast cancer. Study results clearly show that both inhibition of the PI3K/AKT/mTOR pathway and CDK4/6 are promising ways to improve the efficacy of endocrine treatment in ER-positive breast cancer patients with comparably few side effects. Further clinical trials are needed to identify the patient population who would benefit most from a dual inhibition.

Targeted therapies in breast cancer: New challenges to fight against resistance

“…Inhibitors of downstream pathways like PI3K/AKT/ mTOR and RAS/MEK/ERK are also available for therapeutic purpose as well as agents directed against other tyrosine kinases like SRC, insulin-like-growth-factor [IGF/IGF-receptor (IGFR)], poly-ADP ribose polymerase (PARP) Inhibitors and also matrix metalloproteases (MMPs) which are involved in cancer cell invasion and metastasis[8,29,31,44-48]. …”

High levels of sphingolipids in human breast cancer

“…These have the capacity to regulate critical molecular mechanisms of breast cancer growth such as cell cycle, cell survival, DNA double strand breaks repair or tumor immunology [1–4]. Despite these advances in breast cancer therapy, approximately 40,000 women still die from breast cancer every year in the United States and breast cancer remains the leading cause of cancer related death for women aged 20 to 59 years in the world [5].…”

The prognostic and predictive value of the lymphocyte to monocyte ratio in luminal-type breast cancer patients treated with CEF chemotherapy

“…Despite improvements in treatment, the morbidity and mortality rates in luminal breast cancer remain high [4–5]. Recent breakthroughs in cancer immunology substantiated that the host immune system correlates with cancer development and progression, and immunomodulating therapy has emerged as an effective novel therapeutic strategy [6–9].…”