Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer
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Targeting CDK4/6 in breast cancer
Dysregulation of the cell cycle machinery, particularly the overactivation of cyclin-dependent kinases 4 and 6 (CDK4/6), is a hallmark of breast cancer pathogenesis. The introduction of CDK4/6 inhibitors has transformed the treatment landscape for hormone receptor-positive breast cancer by effectively targeting abnormal cell cycle progression. However, despite their initial clinical success, drug resistance remains a significant challenge, with no reliable biomarkers available to predict treatment response or guide strategies for managing resistant populations. Consequently, numerous studies have sought to investigate the mechanisms driving resistance to optimize the therapeutic use of CDK4/6 inhibitors and improve patient outcomes. Here we examine the molecular mechanisms regulating the cell cycle, current clinical applications of CDK4/6 inhibitors in breast cancer, and key mechanisms contributing to drug resistance. Furthermore, we discuss emerging predictive biomarkers and highlight potential directions for overcoming resistance and enhancing therapeutic efficacy.
TFF3 facilitates dormancy of anti-estrogen treated ER+ mammary carcinoma
Tumor dormancy is a substantial clinical obstacle in treatment of estrogen receptor positive mammary carcinoma (ER+MC), contributing to drug resistance, metastatic outgrowth, relapse, and consequent mortality.
LRP11-AS1 mediates enterotoxigenic Bacteroides fragilis-related carcinogenesis in colorectal Cancer via the miR-149-3p/CDK4 pathway
Long noncoding RNAs (lncRNAs) are critical in tumorigenesis and show potential for tumor diagnosis and therapy. Enterotoxigenic Bacteroides fragilis (ETBF), known for producing enterotoxins, is implicated in human gut tumorigenesis, yet the underlying mechanisms are not fully elucidated. This study aims to clarify the molecular mechanisms by which lncRNAs contribute to ETBF-induced tumorigenesis, with a focus on LRP11-AS1’s role in modulating ETBF’s colorectal carcinogenesis. We found a marked increase in LRP11-AS1 expression in colorectal cancer (CRC) tissues compared to adjacent non-tumorous tissues. In vitro, CRC cells exposed to ETBF showed elevated LRP11-AS1 levels. Mechanistically, LRP11-AS1 was shown to enhance CDK4 expression by competitively binding to miR-149-3p. These results indicate that LRP11-AS1 may facilitate ETBF-related carcinogenesis in CRC and could serve as a therapeutic target and diagnostic biomarker for ETBF-associated CRC.
Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies
Transcriptional dysregulation is a hallmark of cancer initiation and progression, driven by genetic and epigenetic alterations. Enhancer reprogramming has emerged as a pivotal driver of carcinogenesis, with cancer cells often relying on aberrant transcriptional programs. The advent of high-throughput sequencing technologies has provided critical insights into enhancer reprogramming events and their role in malignancy. While targeting enhancers presents a promising therapeutic strategy, significant challenges remain. These include the off-target effects of enhancer-targeting technologies, the complexity and redundancy of enhancer networks, and the dynamic nature of enhancer reprogramming, which may contribute to therapeutic resistance. This review comprehensively encapsulates the structural attributes of enhancers, delineates the mechanisms underlying their dysregulation in malignant transformation, and evaluates the therapeutic opportunities and limitations associated with targeting enhancers in cancer.
Targeting of TAMs: can we be more clever than cancer cells?
With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.
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