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

Abstract

Triple positive breast cancers overexpress both the human epidermal growth factor receptor 2 (HER2) oncogene and the hormonal receptors (HR) to estrogen and progesterone. These cancers represent a unique therapeutic challenge because of a bidirectional cross-talk between the estrogen receptor alpha (ERα) and HER2 pathways leading to tumor progression and resistance to targeted therapy. Attempts to combine standard of care HER2-targeted drugs with antihormonal agents for the treatment of HR+/HER2+ breast cancer yielded encouraging results in preclinical experiments but did improve overall survival in clinical trial. In this review, we dissect multiple mechanisms of therapeutic resistance typical of HR+/HER2+ breast cancer, summarize prior clinical trials of targeted agents, and describe novel rational drug combinations that include antihormonal agents, HER2-targeted drugs, and CDK4/6 inhibitors for treatment of the HR+/HER2+ breast cancer subtype.

Curcumin: Modulator of Key Molecular Signaling Pathways in Hormone-Independent Breast Cancer

“…Cancer as the complex disease is a major cause of morbidity and mortality around the world, with 9.9 million deaths in 2020, and has been considered as the world's biggest killer by the age of 70 years in most countries in 2019. The world cancer burden is still Cancers 2021, 13, 3427 2 of 29 increasing, with an estimated occurrence of 28.4 million new cancer cases in 2040, which is an increase of about 47% compared to 2020 globally [1,2]. Among the various types of cancer, breast cancer remained the most frequently occurring cancer among women worldwide, with 2,261,419 newly diagnosed cases in 2020, accounting for 1 in 4 cancer cases, and has now surpassed lung cancer in global cancer incidence.…”

“…However, the overexpression of HER2, a tyrosine kinase receptor mediating cell proliferation and survival, occurs in about 15–30% of breast cancer. HER2-positivity has been more frequently reported in HR- compared to HR+ cancers correlated with an aggressive disorder and poor prognosis [ 12 , 13 , 14 ]. Although HER2-targeted therapies have dramatically improved the overall survival among hormone-independent HER2+ patients, drugs-related side effects are yet major obstacles ahead [ 12 , 15 , 16 ].…”

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer

“…The two objective responses (both PRs) in the combination cohorts are noteworthy because advanced metastatic triple-positive breast cancer is associated with treatment resistance [ 31 ], and AKT1 tumor alterations are associated with resistance to tamoxifen [ 32 ]. Therefore, there is an unmet need for effective treatments in these populations, and further investigation of these combinations is warranted.…”

New Therapeutic Strategies in Advanced Nonoperable or Metastatic HER2-positive Breast Cancer

“…Indeed, there appears to be a complex interplay not only between the cell cycle and ER expression, but also with the HER2 signalling pathway. Evidently the CDK4/6 inhibitors are able to reverse HER2 resistance 23 , 24 . We refer to the monarcHER trial – where the triple combination of fulvestrant/trastuzumab/abemaciclib was superior to combined chemotherapy plus trastuzumab and significantly reduced the risk of progression by 37% (HR 0.63; p = 0.05) 25 .…”

“…Tatsächlich scheint nicht nur ein komplexes Zusammenspiel zwischen dem Zellzyklus und der ER-Expression, sondern auch mit dem HER2-Signalweg zu bestehen. CDK4/6-Inhibitoren scheinen in der Lage zu sein, eine HER2-Resistenz aufzuheben 23 , 24 . Verwiesen sei auf die monarcHER-Studie – hier war die 3er-Kombination Fulvestrant/Trastuzumab/Abemaciclib der Kombination aus Chemotherapie plus Trastuzumab überlegen und reduzierte das Progressionsrisiko signifikant um 37% (HR 0,63; p = 0,05) 25 .…”