The adaptive resistome in triple-negative breast cancer: Identification of mechanisms and functional targeting

• Applicants: Professorin Dr. Kerstin Borgmann; Professor Dr. Nils Cordes; Professor Dr. Mahmoud Toulany
• Subject Area: Radiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467414153

Breast cancer is the most common type of cancer found in women. The cure rates are comparatively high relative to other cancer types and depend on the immunohistochemically defined subtype. Triple-negative breast cancer (TNBC; lacking estrogen receptor (ER), progesterone receptor (PgR), HER2) accounts for 15-20% of all breast cancer cases, presents highly aggressive and with elevated rates of relapse, metastases and early death. Responsible for the poor prognosis is the severe and mechanistically not understood inter-patient heterogeneity based on high mutation rates in, for example, TP53, PIK3CA and BRCA1. While targeted therapies and radiotherapy are currently evaluated in clinical trials, conventional chemotherapy remains the mainstay of treatment. Irrespectively, TNBC is a cancer type of great unmet need and a prime example that resistance to therapy remains one of the most challenging obstacles in cancer. Inherent or acquired therapy resistance evolves from complex interactions between various mechanisms controlled by cellular and non-cellular factors. In addition to gene mutations and microRNAs as cellular factors, micromilieu-associated factors like growth factors and extracellular matrix (ECM) are well known resistance determinants and potent inducers of pro-survival adaptation processes that elicit differential therapy resistance in cancer bulk versus stem cells. This is similarly true for the adaptive resistance induced by radiochemotherapy about which in-depth knowledge is desperately required for fostering the development of functionally optimize therapies. Hence, the aims of this study are to identify druggable DNA repair-, adhesion- and RTK-related candidates of the adaptive, radiochemotherapy-induced resistome in TNBC and to systematically evaluate the cytotoxic and radiochemosensitizing potential of a functional multi-targeting of these candidates. Combined with bioinformatic analyses of generated miRNAs, transcriptome and kinome patterns, wet lab experiments are conducted in organoids derived from TNBC patient biopsies as well as in established TNBC cell lines. To secure more physiological growth conditions, cells are cultured in three-dimensional matrix. Following the elucidation of the underlying mechanisms of the most promising target candidate from each are of signaling, a bioinformatic validation with TCGA data from patients with TNBC takes place with the aim of identifying an adaptom-specific biomarker signature of the most important inhibitable candidates. Through the discovery of novel targets in the radiochemotherapy-induced adaptive resistome and their related mechanisms, we anticipate that our collaborative approach will reveal new key insights into the radiochemoresistance of TNBC, which might be exploitable for developing novel potent functional multi-targeting concepts in combination with conventional radiochemotherapy.

• DFG Programme: Research Grants