Overcoming Chemoresistance in Triple-negative Breast Cancer: New Strategies View PDF

TNBC is a particularly aggressive subtype of breast cancer characterized by the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 [1-5]. This subtype accounts for approximately 15% to 20% of all breast cancer cases and is associated with a high rate of metastasis and poor prognosis due to its inherent chemoresistance [6]. Overcoming chemoresistance in TNBC remains a formidable challenge due to its aggressive nature and limited therapeutic options. Recent research efforts have focused on elucidating molecular mechanisms underlying resistance and developing targeted strategies to enhance chemosensitivity. The collective findings from various studies highlight promising avenues, including molecular targeting, combination therapies, nanotechnologybased delivery systems, and drug repurposing, which collectively contribute to advancing treatment paradigms for TNBC [7-9].

One of the pivotal approaches involves targeting specific molecular pathways that confer resistance. Haritha et al. [10] identified thymidylate synthase as a critical target, demonstrating that pharmacological inhibition of thymidylate synthase enhances the chemosensitivity of TNBC cells to 5-fluorouracil. Their preclinical studies confirmed the safety of this combinatorial approach, advocating for clinical validation, especially given the paucity of effective options for TNBC patients. Similarly, Rodriguez et al. [11] explored substance P receptor antagonism in combination with cisplatin, revealing that this strategy not only potentiates cisplatin efficacy but also offers protective effects against oxidative stress and apoptosis in neuronal and TNBC cell lines. These findings underscore the potential of receptor antagonists as adjuncts to conventional chemotherapy.

Further insights into resistance mechanisms have been gained through the investigation of specific signaling pathways and gene regulators. Jiang et al. [12] elucidated the role of the TBX15/miR- 152/KIF2C pathway in doxorubicin resistance, demonstrating that modulation of this axis influences PKM2 ubiquitination and, consequently, drug sensitivity. Similarly, Mehlich et al. [13] identified MLK4 as a promoter of DNA damage response and chemoresistance, with MLK4 inhibition sensitizing TNBC cells to DNA-damaging agents. These studies highlight the importance of targeting intracellular signaling and repair pathways to overcome resistance.

CSCs have also been recognized as key contributors to chemoresistance and metastasis. He et al. [14] provided a comprehensive overview of the molecular landscape of breast CSCs (BCSCs), emphasizing the need to develop therapies that target these subpopulations to prevent relapse and dissemination. The identification of specific biomarkers and signaling pathways in BCSCs offers promising targets for future therapies aimed at eradicating resistant cell populations. In addition to molecular targeting, modulation of the TME and immune landscape has gained attention. Wu et al. [15] reviewed plant-derived natural products that modulate immune responses and tumor metabolism, suggesting their potential in reprogramming the TME to favor anti-tumor activity. Such agents could complement existing therapies by enhancing immune-mediated tumor clearance.

Innovative drug delivery systems have also been developed to improve therapeutic efficacy and reduce toxicity. Date et al. [16] designed dual-action cisplatin(IV) prodrugs conjugated with bioactive moieties, which demonstrated superior tumor reduction in TNBC models compared to cisplatin alone. Similarly, Cho et al. [17] developed albumin-binding peptide-drug conjugates exploiting PTEN-loss pathways, facilitating targeted delivery and bystander killing effects in metastatic TNBC. These nanotechnology-based approaches aim to enhance drug accumulation within tumors and target multiple cellular pathways simultaneously. Drug repurposing strategies have emerged as a rapid means to identify effective agents against resistant TNBC. Sari et al. [18] identified proteasome inhibitors, such as bortezomib and carfilzomib, through high-throughput screening, which suppressed TNBC organoid growth by impairing translation and cell cycle progression. Likewise, López-Tejada et al. [19] focused on transcriptomic signature-based drug repurposing, identifying compounds that mimic the effects of TGF-β pathway inhibition, which is implicated in tumor progression and resistance.

Targeting specific resistance-associated genes has also shown promise. Ogbu et al. [20] demonstrated that knockout of DSTYK via CRISPR/Cas9 induces apoptosis in chemoresistant cells, suggesting that DSTYK could serve as a therapeutic target. Similarly, Wang et al. [21] linked high CENPF expression to poor prognosis and chemoresistance, indicating that CENPF suppression might restore chemosensitivity. Furthermore, Zhou et al. [22] uncovered the role of METTL3/IGF2BP3-mediated m6A modification of HYOU1 in conferring doxorubicin resistance, providing a novel epigenetic target for overcoming resistance. The role of BCSCs in chemoresistance has been further elucidated by He et al. [14], who emphasized the importance of targeting BCSC-specific pathways and biomarkers. Strategies such as differentiation therapy, as explored by Wu et al. [23], involve transforming resistant stem-like cells into more differentiated, chemosensitive states, thereby indirectly eradicating the resistant subpopulation.

Finally, the integration of multi-targeted approaches appears promising. Cheng et al. [24] identified protein kinase C as a therapeutic target to restore Aurora kinase B expression, thereby overcoming paclitaxel resistance. Similarly, dual metabolic inhibition of glutaminase and xCT by Choi et al. [25] successfully sensitized resistant TNBC cells, highlighting the potential of metabolic reprogramming in overcoming chemoresistance. Overall, the multifaceted nature of chemoresistance in TNBC necessitates a combination of targeted molecular therapies, innovative drug delivery systems, and drug repurpose strategies. The studies reviewed demonstrate that targeting specific pathways such as thymidylate synthase, MLK4, DSTYK, and epigenetic modifications, alongside approaches that eliminate CSCs and modulate the TME, hold significant promise. The development of nanotechnology-based delivery systems and the repurposing of existing drugs further expand the arsenal against resistant TNBC. Collectively, these strategies pave the way for more effective, personalized treatments aimed at overcoming chemoresistance and improving patient outcomes in TNBC.