The triple-negative breast cancer (TNBC) accounts for approximately 15% to 20% of all breast carcinomas with a worse prognosis, high aggression and early metastasis [[1], [2], [3]]. Due to the lack of receptors for progesterone and estrogen hormones and non-overexpress the human epidermal growth factor receptor 2 (HER2) protein, there are no targeted therapies for TNBC, so chemotherapy still remains the reference treatment of nonsurgical TNBC [2]. The 5-year survival rate of regional tumors in TNBC is 65%, and the distant organ metastasis is only 11% [4,5]. Therefore, there is an urgent need to develop precise therapeutic drugs for the treatment of TNBC.

Poly(ADP-ribose) polymerases (PARPs), which constitute a large family of 18 proteins [6], are essential for DNA repair and also play a crucial role in cellular differentiation, gene transcription, inflammation, mitosis, cell death, and metabolism [[7], [8], [9]]. Among them, PARP1 accounting for 90% of total cellular PARP activity is considered crucial for DNA base excision repair and repair of DNA single-strand breaks (SSBs) [7,10,11]. Double-strand breaks (DSBs) are another DNA damage response, and homologous recombination (HR) pathway is the most “faithful” repair pathway to trig precise repair of DSBs [12,13]. Meanwhile, breast cancer gene 1/2 (BRCA1/2) [14] regulates HR repair of DNA double-strand breaks (DSBs) [13,15]. Therefore, tumor cells with BRCA1/2 mutations can only rely on alternative DNA repair pathways and are susceptible to chemical inhibitors of PARP1, which is the concept of synthetic lethality [16]. It's worth noting that there are many phenotypic characteristics between TNBC and BRCA1-mutated tumors [17]. And clinical data indicate that more than 80% of breast cancer patients with a hereditary BRCA1 mutation are TNBC [18]. Many preclinical and clinical studies have also shown that tumor cells lacking functional BRCA1 or BRCA2 exhibit sensitivity to PARP1 inhibition [[19], [20], [21]]. Therefore, PARP1 inhibitors are regarded as the most promising drugs for targeted therapy of TNBC [22]. In recent years, several small molecule PARP1 inhibitors (PARPi), including Senaparib, Olaparib, Niraparib, Pamiparib, Talazoparib, Fluzoparib, Rucaparib, have been approved by FDA or NMPA for the treatment of various types of BRCA1/2 mutated cancers, such as ovarian cancer, breast cancer and prostate cancer [23] (Fig. 1A). However, although these BRCA-mutated tumors are sensitive to PARP1i, they will eventually develop acquired resistance with prolonged oral administration of PARPi [24]. In addition, more than 40% BRCA1/2-deficient patients fail to respond to PARPi [19,25]. And approximately 80% of TNBC patients do not have BRCA mutations [26,27]. Therefore, how to increase the response rate of TNBC to PARP1 inhibitors and expand the use of PARP1 inhibitors beyond patients with BRCA-mutated TNBC is in urgent need [28,29].

The c-mesenchymal-to-epithelial transition factor (c-Met) is a member of the transmembrane receptor tyrosine kinases (RTKs), which is also known as hepatocyte growth factor receptor (HGFR) [30]. Its ligand hepatocyte growth factor (HGF)/scatter factor (SF) binding to the extracellular domain of c-Met favors the receptor dimerization and tyrosine autophosphorylation (Y1234 and Y1235), and activation of several downstream signal transduction pathways. c-Met is a key regulator of various biological processes including cell proliferation, migration, mitogenesis, morphogenesis, and angiogenesis [31,32]. To date, the development of c-Met-TKIs has achieved remarkable success, and a total of c-Met inhibitors have been approved. Capmatinib and Tepotinib are the earliest selective c-Met inhibitors approved by FDA for the treatment of lung cancer [33,34] (Fig. 1B). Savolitinib is the first selective c-Met inhibitor approved by NMPA for the treatment of metastatic non-small cell lung cancer (NSCLC) with MET exon 14-skipping alterations. With the increasing number of c-Met inhibitors approved, c-Met has received more and more attention as a promising cancer therapeutic target.

In preclinical studies, c-Met plays a key role in transmitting oncogenic signals in TNBC [35]. Furthermore, the expression of c-Met is closely related to the poor survival rate and poor prognosis of patients with TNBC [36]. Recent studies have shown that high levels of reactive oxygen species (ROS) in TNBC lead to overexpression of c-Met, followed by phosphorylation of PARP1 at Y907, resulting in increased activity of PARP1 and attenuated inhibitory effect of PARP1 inhibitors to ultimately lead to intrinsic resistance [37]. Additionally, c-Met critically contributes to error-free HR repair of DSB and can effectively enhance the DNA repair function of PARP1 in BRCA wild-type TNBC [38,39]. These results suggested that targeting c-Met might be effective approach to enhance the sensitivity of BRCA wild-type TNBC to PARP1 inhibitors (Fig. 2A). Immediately after that, the first-in-class PARP1/c-Met dual inhibitors were disclosed by Zhu to overcome PARP1 inhibitor resistance induced by c-Met overexpression [40,41]. Inspired by these findings, a series of c-Met/PARP dual-target inhibitors were designed for the treatment of BRCA wild-type TNBC to expand the application of PARP1 inhibitors.