Systematic therapy of platinum-based chemoradiotherapy has occupied the backbone role in the management of SCLC for decades. Currently, extensive research has been conducted in the field of targeted therapy for SCLC, focusing on the abnormal signaling pathways involved in cell cycle and DNA damage and repair (DDR), epigenetic regulation, cell metabolism, and tumor immunity. Despite the exploration of numerous drugs targeting various pathways for treating SCLC, only ICIs have demonstrated satisfied efficacy. Subsequently, we will present a comprehensive review for these studies. Due to the profound significance and unique characteristics of immunotherapy, it will be discussed in detail as a separate topic. Key completed and ongoing trials targeting various pathways, including the cell cycle and DDR pathway, epigenetics, metabolism, as well as NOTCH pathway and apoptosis, are shown in Tables 2 and 3, categorized by target and agent.

Table 2 Key completed trials for SCLC categorized by targetTable 3 Ongoing clinical trials for SCLC categorized by target and agentCell cycle and DNA damage and repair

The frequent loss of RB1 and TP53 in SCLC renders this tumor more vulnerable to DNA damage, thus leading to the upregulation of mediators involved in cell cycle control and the DDR pathway to maintain genomic instability and evade cell death [102]. Inhibition or loss of DDR proteins exacerbates the accumulation of DNA damage and increases the susceptibility of SCLC to various agents that cause DNA damage [103]. Therefore, DDR proteins such as PARP, ATR, CHK1 and WEE1 have been identified as potential targets for SCLC treatment.

Poly (ADP-ribose) polymerase, PARP

PARP is a prominent drug target among DDR proteins [104]. PARP inhibitors impede DNA repair and synergize with drugs that induce DNA damage. Additionally, PARP inhibition significantly upregulates PD-L1 expression and augments the antitumor effect of ICIs through the STING-mediated immune pathway [105, 106]. Thus, extensive investigations have been conducted to evaluate the addition of PARP inhibitors to standard chemoradiotherapy, immunotherapy, or other DNA damage agents for the treatment of SCLC [107]. Currently, PARP inhibitors that have been utilized in clinical trials for SCLC mainly include olaparib, talazoparib, veliparib, niraparib, fluzoparib, rucaparib, AZD5305 and RP12146.

PARP inhibitors are primarily used as subsequent therapeutic options after the initial treatment of extensive-stage SCLC (ES-SCLC). The efficacy of PARP inhibitor monotherapy as maintenance therapy is limited, resulting in relatively few studies [108,109,110,111]. The combination of temozolomide (TMZ) with the PARP inhibitors veliparib or olaparib was investigated in relapsed SCLC patients in two phase 2 trials. The results revealed that the addition of PARP inhibitors enhances the antitumor effect of TMZ, but no significant OS benefit has been observed (OS 8.2 months vs. 7.0 months, P = 0.50) [112, 113]. The efficacy of olaparib combined with durvalumab was tested in two single-arm trials involving relapsed ES-SCLC patients, but these trials did not meet their primary efficacy endpoints [114, 115]. PARP inhibitors have also been investigated as first-line treatment regimens for SCLC. In two phase 2 trials, the addition of veliparib to platinum-based frontline chemotherapy improved progression-free survival (PFS) in treatment-naïve patients with ES-SCLC [116, 117].

The combination of chemotherapy and immunotherapy has emerged as the recommended first-line treatment for ES-SCLC [4, 118]. In this setting, the addition of PARP inhibitors is currently being investigated in several ongoing clinical trials (NCT05245994, NCT04728230, and NCT04624204). Given the diverse responses observed in finished trials, it is important to identify patients who may benefit from PARP inhibitors. Focusing on patients who are sensitive to chemotherapy seems to be a promising approach (NCT03923270, NCT05162196, NCT03830918, NCT04782089, and NCT03958045). In addition, biomarkers play a significant role in predicting the response to PARP inhibitors. Increased sensitivity to PARP inhibitors is associated with increased SLFN11 expression [112, 119,120,121], decreased EMT scores and E-cadherin levels [122], decreased DNA-PKcs expression [123], increased E2F1 expression [102], decreased ATM expression [122] and the use of fluorinated [18F]-radiolabeled PARPis [124]. However, among these biomarkers, only SLFN11 has been applied for patient selection in ongoing trials (NCT05718323, NCT04334941).

In general, as valuable drugs targeting the DDR pathway, PARP inhibitors exacerbate tumor susceptibility by inhibiting DNA repair, aggravating DNA damage and enhancing tumor immunity, thereby achieving promising efficacy in first-line treatment of SCLC. In the future, guided by subtype-specific therapy, ASCL1-subtype with high levels of SLFN11 may represent a prioritized population for PARP inhibitors.

Ataxia telangiectasia and Rad3-related protein, ATR

As a crucial component of DDR proteins, ATR plays a pivotal role in sensing DNA damage and preserving genomic instability [125, 126]. Upon activation by DNA damage, ATR stops cell progression to the G2 phase through the G2/S checkpoint, thereby preventing cell apoptosis [127]. Three ATR inhibitors, berzosertib (M6620), ceralasertib (AZD6738) and elimusertib (BAY1895344), have been investigated in SCLC. The combination of ATR inhibitors with DNA TOP1 inhibitors was found to augment their antitumor efficacy and potentially improve the response to immunotherapy in SCLC characterized by low expression of the STING pathway [101, 128]. In single-arm trials, berzosertib combined with topotecan achieved good tolerance and critical clinical benefit in relapsed platinum-resistant SCLC patients [101, 129]. Recently, a two-arm phase 2 trial demonstrated that berzosertib plus topotecan did not improve PFS (HR = 0.80 [95% CI 0.46–1.41]; P = 0.44) in relapsed SCLC patients compared to topotecan alone, but it significantly prolonged OS (HR = 0.53 [95% CI 0.29–0.96]; P = 0.03) [130]. Two trials (NCT03428607, NCT02937818) investigated the combination of AZD6738 and olaparib in relapsed or refractory SCLC patients; however, neither achieved the predetermined therapeutic endpoint [108].

Ongoing trials are currently investigating the safety and efficacy of berzosertib combined with topotecan (NCT04768296), irinotecan (NCT02595931), or sacituzumab govitecan (NCT04826341) in relapsed SCLC patients. A previous study identified an ATR inhibitor as the most effective agent for potentiating lurbinectedin in SCLC [131]. Further clinical trials are underway to confirm its safety and efficacy in relapsed SCLC patients (NCT04802174). The addition of AZD6738 to immunotherapy as a second/third-line treatment (NCT04361825) or chemoimmunotherapy as a first-line treatment (NCT04699838) is under investigation in single-arm trials. The results of an epigenome-wide DNA methylation analysis suggested that sensitivity to ATR inhibitors may be correlated with genomic methylation levels and TREX1 expression [132]. To date, no biomarker-guided trial has been identified.

Overall, ATR inhibitors exert anti-tumor effects by promoting apoptosis induced by DNA damage and enhancing tumor immunity. The combination of ATR inhibitors with topotecan, lurbinectedin or immunotherapy has potential advantages in relapsed SCLC. However, further evidence is needed to better understand the role of ATR inhibitors in subtype-specific therapy.

Checkpoint kinase 1, CHK1

CHK1 is a serine/threonine protein kinase involved in DNA damage-induced cell cycle arrest and is considered as a potential therapeutic target for SCLC [133,134,135]. Currently, the CHK1 inhibitors utilized in the treatment of SCLC patients include prexasertib (LY2606368) and SRA-737. In both SCLC cells and mouse models, promising antitumor efficacy has been achieved by CHK1 inhibitor monotherapy or in combination with chemotherapy or PARP inhibition. These findings highlight the potential of CHK1 inhibitors to overcome resistance to chemotherapy or PARP inhibitors [99, 136,137,138]. In addition, CHK1 inhibition activates the function of cytotoxic T lymphocytes via the innate immune STING pathway and enhances the antitumor effect of ICIs [105].

The recommended dose of LY2606368 monotherapy was established in a phase 1 trial, but a subsequent phase 2 trial failed to achieve the anticipated efficacy in platinum-resistant ES-SCLC patients [139, 140]. Another oral CHK1 inhibitor, i.e., SRA-737, was tested in a phase 1/2 trial. The combination of SRA-737 and low-dose gemcitabine resulted in a partial response rate of 11.1% (1/9) in SCLC patients [141]. Furthermore, the addition of SRA737 and low-dose gemcitabine enhances the antitumor efficacy of PD-L1 blockade, highlighting a potential triple combination therapy [142]. The inhibition of WEE1 reversed LY2606368 resistance in SCLC cell lines, thereby providing evidence for the synergistic potential of CHK1 and WEE1 inhibitors [143].

To sum up, CHK1 inhibitors impede DNA damage repair, resulting in the formation of replication barriers and induction of apoptosis in cancer cells. However, the efficacy of CHK1 inhibitors for SCLC remains unsatisfactory. The overexpression of MYC has been identified as a candidate biomarker for CHK1 inhibitors [99, 144]. Thus, despite suboptimal performance, CHK1 inhibitors may be applicable to NEUROD1 and other ASCL1-low subtypes characterized by MYC overexpression.

WEE1

WEE1 is a protein tyrosine kinase that inactivates cyclin-dependent kinase (CDK) 1/2 in the cell cycle and protects against DNA replication through the regulation of histone synthesis and epigenetic modification [145,146,147]. The combination of a WEE1 inhibitor and a PARP inhibitor exhibits promising antitumor efficacy within circulating tumor cell (CTC)-derived explant SCLC models [148, 149]. Inhibition of WEE1 promotes the immune response via the STING-TBK1-IRF3 pathway, enhances the antitumor effect of PD-L1 antibodies through the STAT1 pathway, and significantly suppresses tumor progression in SCLC models (including MYC-stabilized SCLC) [150].

Adavosertib (AZD1775) is an oral WEE1 inhibitor that has been tested in several advanced solid tumors. In a three-arm trial (NCT02937818), the efficacy of AZD1775 in combination with carboplatin was evaluated in platinum refractory ES-SCLC patients, with a median OS of 4.67 months, indicating the potential efficacy in SCLC. An ongoing trial is investigating the safety and efficacy of the novel WEE1 inhibitor Debio-0123 in combination with etoposide and carboplatin in patients with relapsed SCLC (NCT05815160).

In summary, WEE1 does not appear to be a worthy target in the treatment of SCLC, as the efficacy of WEE1 inhibitors is quite limited and its potential has yet to be fully explored in subtype-specific therapy.

Aurora kinase A/B, AURKA/B

The aurora kinase family is classified as serine/threonine kinases that play crucial roles in regulating the G2/M transition and spindle assembly checkpoint during the cell cycle [151]. RB1 gene mutations and MYC overexpression or amplification frequently occur in SCLC, leading to high sensitivity to AURKA/B inhibitors [39, 91, 144, 152,153,154]. A recent study demonstrated the potential of AURKA/B inhibitors to augment the antitumor efficacy of PD-L1 blockade via the restoration of inflammatory gene expression [155]. Currently, three AURKA inhibitors, namely, alisertib (MLN8237), JAB-2485, and erbumine (LY3295668), are used to treat SCLC.

A multicenter phase 1/2 trial investigated the efficacy of the oral AURKA inhibitor alisertib as monotherapy in advanced tumors. Among 48 relapsed SCLC patients, 10 (20.8%) achieved an objective response, and a median FPS of 2.1 months was observed [156]. In a separate phase 1 trial, alisertib was combined with nab-paclitaxel, resulting in a partial response in 1 out of 5 refractory SCLC patients [157]. In a phase 2 trial, the combination of alisertib and paclitaxel as a second-line treatment demonstrated superior PFS benefits for patients with relapsed SCLC expressing MYC compared to monotherapy with paclitaxel (PFS 4.6 months vs. 2.3 months; HR = 0.29, 95% CI 0.12–0.72) [158]. An ongoing phase 2 trial (NCT06095505) is evaluating the safety and efficacy of alisertib in progressed ES-SCLC patients who are receiving or have completed first-line treatment with chemotherapy combined with anti-PD-L1 immunotherapy. Further ongoing trial will determine the role of AURKA inhibitor.

In conclusion, AURKA inhibitors present promising antitumor efficacy through the inhibition of MYC. AURKA may be considered as a potential therapeutic vulnerability for NEUROD1, POU2F3 and Inflamed subtypes based on the transcriptional classification, and nmf4 subtype based on the multi-omics classification that exhibit overexpression of MYC in subtype-specific therapy.

Cyclin-dependent kinase 4/6, CDK4/6

The aberrant activation of CDK4/6 results in excessive phosphorylation of the Rb protein, leading to dysregulation of the G1/S transition and promoting tumorigenesis [159,160,161]. The antitumor effect of CDK4/6 inhibitors has not been confirmed in SCLC, but they have shown strong protective effects against chemotherapy-induced myelosuppression (CIM) [162]. The transient and reversible arrest of hematopoietic stem and progenitor cells (HSPCs) in the G1 phase is achieved through the inhibition of CDK4/6, thereby providing protection against cytotoxic injury induced by chemotherapy [163]. Several clinical trials have demonstrated the protective effects of the CDK4/6 inhibitor trilaciclib in CIM [164,165,166]. Thus, the Food and Drug Administration (FDA) has granted approval to trilaciclib for alleviating CIM in ES-SCLC patients [167]. Additionally, the incorporation of trilaciclib into chemotherapy plus ICIs effectively preserved immune system function and augmented the antitumor response in preclinical models [168].

An ongoing phase 4 trial is evaluating progression and survival in ES-SCLC patients when trilaciclib is added to topotecan-containing chemotherapy (NCT05874401). The effect of trilaciclib in combination with lurbinectedin is currently being investigated in a phase 2 trial (NCT05578326). The efficacy and safety of abemaciclib, a novel CDK4/6 inhibitor, are under evaluation in Rb wild-type refractory ES-SCLC (NCT04010357). All in all, although CDK4/6 inhibitors do not specifically target any subtypes, they hold significant and extensive implications as protective agents to alleviate the adverse effects of chemotherapy.

Epigenetics

The accumulation of genomic structural and functional changes is widely recognized as a primary force driving cancer development. Epigenetic modification represents one such mechanism. Epigenetic modifications are characterized by heritable changes in gene activity that occur without altering the DNA sequence. Abnormal modifications regulate gene expression patterns that promote tumorigenesis and facilitate the acquisition of hallmark tumor capabilities [169]. The two primary types of epigenetic modifications are DNA methylation and histone modifications. Clinicians are leveraging these events as adjunctive tools in clinical decision-making. Furthermore, the reversibility of epigenetic modifications has led to the emergence of epigenetic therapy as a promising strategy for treating SCLC [170, 171].

Lysine-specific demethylase 1, LSD1

As a form of histone modification, histone methylation represents one of the critical epigenetic hallmarks of SCLC. Encoded by KDM1A, LSD1 functions as a histone demethylase that selectively removes monomethylated and dimethylated groups from histone H3K4 and H3K9 sites, thereby influencing gene transcription [172]. Through interaction with SNAG domain-containing proteins, namely, INSM1 and GFI1B, LSD1 facilitates the transcriptional activation of genes associated with NE phenotypes and augments the proliferation of SCLC cells. Perturbation of this interaction attenuates the expression of pivotal genes, such as ASCL1, and impedes tumor proliferation [173]. Similarly, ZFP36L1 has been identified as a target gene of LSD1, which binds to and destabilizes SOX2 and INSM1, thus regulating the NE differentiation of SCLC cells [174]. A recent study demonstrated that LSD1 inhibition activates NOTCH signaling, leading to a subsequent reduction in ASCL1 expression in SCLC [95]. Additionally, the selective LSD1 inhibitor GSK2879552 was found to induce growth inhibition in SCLC cell lines [175]. These findings underscore the potential of LSD1 as a therapeutic target for SCLC.

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