Genomic instability is a core characteristic of cancer, often stemming from defects in DNA damage response (DDR) or increased replication stress. DDR defects can lead to significant genetic alterations, including changes in gene copy numbers, gene rearrangements, and mutations, which accumulate over time and drive the clonal evolution of cancer cells. However, these vulnerabilities also present opportunities for targeted therapies that exploit DDR deficiencies, potentially improving treatment efficacy and patient outcomes. The development of PARP inhibitors like Olaparib has significantly improved the treatment of cancers with DDR defects (e.g., BRCA1 or BRCA2 mutations) based on synthetic lethality. This achievement has spurred further research into identifying additional therapeutic targets within the DDR pathway. Recent progress includes the development of inhibitors targeting other key DDR components such as DNA-PK, ATM, ATR, Chk1, Chk2, and Wee1 kinases. Current research is focused on optimizing these therapies by developing predictive biomarkers for treatment response, analyzing mechanisms of resistance (both intrinsic and acquired), and exploring the potential for combining DDR-targeted therapies with chemotherapy, radiotherapy, and immunotherapy. This article provides an overview of the latest advancements in targeted anti-tumor therapies based on DDR and their implications for future cancer treatment strategies.

Malignant pleural mesothelioma (MPM) is a lethal cancer with limited treatment options. No targeted therapy has emerged yet. Here, we performed an integrated molecular characterization of patient tumors in the TCGA dataset, and discovered that endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR) signaling are characteristically deregulated in MPM. Consequently, pharmacological perturbation of ER stress/UPR axis by HA15, an agent that induces persistent proteotoxic stress in the ER, selectively suppresses the viability of MPM cells including those refractory to standard chemotherapy. Mechanically, HA15 augments the already high basal level of ER stress in MPM cells, embarks pro-apoptotic malfunctional UPR and autophagy, which eventually induces cell death in MPM. Importantly, HA15 exerts anti-MPM effectiveness in a mouse model of patient-derived xenografts (PDX) without eliciting overt toxicity when compared to chemotherapy. Our results revealed that programs orchestrating ER stress/UPR signaling represent therapeutic vulnerabilities in MPM and validate HA15 as a promising agent to treat patients with MPM, naïve or resistant to chemotherapy.

KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS‐driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo‐like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS ‐mutant tumor models in vitro and in vivo . Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti‐proliferative effects and cell death in KRAS ‐mutant lung and pancreatic but not colon nor KRAS wild‐type cancer cells. Mechanistically, co‐targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress‐activated c‐Jun N‐terminal kinase (JNK)/p38 pathway and E2F1‐induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS ‐mutant patient‐derived xenografts and a genetically engineered mouse model of Kras ‐induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS ‐mutant cancer.

Background and Purpose: Endothelium‐derived hyperpolarizing factor (EDHF) has been suggested as a therapeutic target for vascular protection against ischaemic brain injury. However, the molecular entity of EDHF and its action on neurons remains unclear. This study was undertaken to demonstrate whether the hydrogen sulfide (H₂S) acts as EDHF and exerts neuroprotective effect via large‐conductance Ca²⁺‐activated K⁺ (BK_Ca/K_Ca1.1) channels.Experimental Approach: The whole‐cell patch‐clamp technology was used to record the changes of BK_Ca currents in rat neurons induced by EDHF. The cerebral ischaemia/reperfusion model of mice and oxygen–glucose deprivation/reoxygenation (OGD/R) model of neurons were used to explore the neuroprotection of EDHF by activating BK_Ca channels in these neurons.Key Results: Increases of BK_Ca currents and membrane hyperpolarization in hippocampal neurons induced by EDHF could be markedly inhibited by BK_Ca channel inhibitor iberiotoxin or endothelial H₂S synthase inhibitor propargylglycine. The H₂S donor, NaHS‐induced BK_Ca current and membrane hyperpolarization in neurons were also inhibited by iberiotoxin, suggesting that H₂S acts as EDHF and activates the neuronal BK_Ca channels. Besides, we found that the protective effect of endothelium‐derived H₂S against mice cerebral ischaemia/reperfusion injury was disrupted by iberiotoxin. Importantly, the inhibitory effect of NaHS or BK_Ca channel opener on OGD/R‐induced neuron injury and the increment of intracellular Ca²⁺ level could be inhibited by iberiotoxin but enhanced by co‐application with L‐type but not T‐type calcium channel inhibitor.Conclusion and Implications: Endothelium‐derived H₂S acts as EDHF and exerts neuroprotective effects via activating the BK_Ca channels and then inhibiting the T‐type calcium channels in hippocampal neurons.

Oncogenic activation of the FGFR pathway is frequent in lung and other cancers. However, due to drug resistance, pharmacological blockage of aberrant FGFR signaling has provided little clinical benefit in patients with FGFR-amplified tumors. The determining factors for the limited efficacy of FGFR-targeted therapy remain incompletely understood. In this study, we performed kinome-wide CRISPR/Cas9 loss-of-function screens in FGFR1-amplified lung cancer cells treated with an FGFR inhibitor. These screens identified PLK1 as a potent synthetic lethal target that mediates a resistance mechanism by overriding DNA damage and cell-cycle arrest upon FGFR1 inhibition. Genetic and pharmacological antagonism of PLK1 in combination with FGFR inhibitor therapy synergized to enhance antiproliferative effects and drove cancer cell death in vitro and in vivo through activation of the γH2AX–CHK–E2F1 axis. These findings suggest a previously unappreciated role for PLK1 in modulating FGFR1 inhibitor sensitivity and demonstrate a synergistic drug combination for treating FGFR1-amplified lung cancer. Significance: The identification of PLK1 as a potent synthetic lethal target for FGFR-targeted therapy provides an innovative rationale for the treatment of lung and other FGFR1-amplified cancers.

KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRAS^G12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable—that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRAS^G12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRAS^G12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRAS^G12C and discuss the challenges of KRAS^G12C inhibitor therapy, as well as future directions.