Table S2. KRAS mutations in leukemia

Table S3. HRAS mutations in leukemia

Although neoadjuvant immunochemotherapy (nICT) improves gastric cancer (GC) outcomes, resistance remains a challenge, highlighting the need for better patient selection and strategies to overcome resistance. Here, we analyze 110 patients with GC before and after nICT or chemotherapy (nCT) from the NEOSUMMIT-01 trial using multi-omic sequencing followed by functional validation. We identify five tumor microenvironment ecotypes (EC1-5) linked to therapy. nICT achieves response in EC1 (T cell activation), EC2 (tertiary lymphoid structures), and EC3 (vascular normalization), but not in EC4 (extracellular matrix organization) and EC5 (immunosuppressive macrophage enrichment). Notably, nICT resistance in EC5 is mediated by the interaction between APOA1+ tumor cells and TREM2+ macrophages. Additionally, we reveal multiple biomarkers associated with nICT efficacy, including SBS19, HLA-B∗15:02, FDXR expression, and FGFR pathway activity, and provide a multi-omic stratification model for treatment response-based patient stratification. This study provides mechanistic insights into nICT in GC, informs therapeutic decisions, and reveals potential targets.

Magnesium serves as an essential cofactor for small GTPases, yet its structural role in regulating KRAS conformational dynamics and nucleotide exchange remains poorly understood. Here, we combine hydrogen-deuterium exchange mass spectrometry (HDX-MS), native mass spectrometry, and functional assays to elucidate how Mg2+ stabilizes the KRAS conformational ensemble and constrains transitions between GDP- and GTP-bound states. Depletion of Mg2+ triggers widespread increases in structural dynamics throughout KRAS-spanning the p-loop, α1-helix, switch I, nucleotide-binding region, and distal helices-revealing a global loosening of the protein fold that favors an open, nucleotide exchange-competent state. Mg2+ titration experiments demonstrate that individual structural elements exhibit distinct Mg2+ dependencies: the p-loop and α1-helix recover native dynamics at micromolar concentrations, whereas switch I requires millimolar levels, underscoring its exceptionally high sensitivity to Mg2+ for structural stabilization. KRAS bound to the catalytic domain of exchange factor SOS1 displays an HDX signature closely resembling the Mg2+-free state, indicating that SOS1 promotes nucleotide exchange by transiently perturbing Mg2+ coordination while simultaneously stabilizing switch I. Consistently, the phosphomimetic KRAS S17E variant, which disrupts a critical Mg2+-coordinating residue, exhibits pronounced global destabilization-reinforcing the central importance of Mg2+ in maintaining structural integrity. Taken together, our findings show that Mg2+ acts as a master regulator of KRAS structural dynamics and reveal Mg2+-sensitive hotspots that might represent promising targets for next-generation KRAS therapeutics.

11539 Background: SDH deficiency causes succinate accumulation and metabolic defects in gastrointestinal stromal tumor (GIST) and paraganglioma. Olverembatinib downregulates lipid uptake protein CD36, restricting fatty acid supply required for SDH-deficient GIST cell growth. We report updated clinical and translational results from study HQP1351SJ0003 (NCT03594422) of olverembatinib in SDH-deficient GIST and paraganglioma. Methods: Patients (pts) (≥ 12 years) with GIST and other solid tumors received olverembatinib 30 to 50 mg PO QOD. Primary cells from tumor tissues of 9 pts with SDH-deficient GISTs were used for ex vivo analyses. All samples were collected at Sun Yat-sen University Cancer Center, with informed consent from pts. Cell migration/invasion was evaluated by wound healing, Transwell migration, and Matrigel invasion assays. Lipid levels were quantitated by LC-MS. Knockdown of CD36 and p38 was done by siRNA. Protein levels were assessed by western blot. Results: As of November 13, 2025, a total of 32 pts, including 26 pts with IHC-confirmed SDH-deficient GIST, had received olverembatinib. The median age of pts with SDH-deficient GIST was 30 (range 13-56) years; 19 (73.1%) were female. Twenty-five pts (96.2%) had received ≥ 1 TKI and 13 (50.0%) ≥ 3. Six (23.1%) pts experienced PR as best response, and the median PFS was 25.7 (range 12.9-NR) months. An additional six pts with paraganglioma had received olverembatinib (all were SDH-deficient as determined by either negative SDHB IHC or SDHB gene mutation). The median age was 47.5 (range 31-61) years; all were male. Best responses were observed in four pts, with SD lasting ≥ 4 cycles (CBR, 66.7%); SD represents meaningful clinical benefit in this slow-growing tumor type. The median PFS was 8.25 (range 1.87-NR) months. SDH-deficiency was associated with a higher risk of tumor metastasis. In SDH-deficient (vs. SDH-competent) GIST cells, significantly higher linoleic acid levels were observed. Supplementation of free fatty acids promoted SDH-deficient cell migration, which could be inhibited by olverembatinib at 30 nM. In addition, siRNA knockdown of p38, a kinase target of olverembatinib, and treatment with two p38 inhibitors significantly downregulated CD36 protein levels, suggesting that p38 regulates cellular CD36. Further, western blot analysis showed that olverembatinib dose-dependently inhibited CD36 protein and phosphorylated p38 protein levels in primary cells from SDH-deficient pts. These findings suggest olverembatinib suppresses fatty acid-promoted migration via the p38-CD36 pathway. Conclusions: Olverembatinib showed sustained clinical efficacy in SDH-deficient GIST and paraganglioma. Mechanistically, olverembatinib inhibits fatty acid–promoted invasion and migration of SDH-deficient GIST by targeting the p38-CD36 signaling pathway. Clinical trial information: NCT03594422 .

4079 Background: Borrmann type IV (Borrmann-IV) gastric cancer (GC), or linitis plastica, is marked by diffuse infiltration, early metastasis, and poor prognosis, with limited benefit from conventional therapies. This study evaluated the efficacy and safety of a total neoadjuvant regimen combining immunotherapy and chemotherapy in Borrmann-IV GC. Methods: This trial (NCT06451211) enrolled patients with Borrmagnn-IV gastric cancer without distant metastasis. Participants received a total neoadjuvant regimen consisting of tislelizumab (an anti–PD-1 antibody) combined with platinum-based chemotherapy (oxaliplatin plus capecitabine or S-1) for 6 cycles at 3-week intervals, followed by radical surgical resection. The prespecified primary endpoint was the pathological response rate, defined as tumor regression grade (TRG) 0/1. Results: A total of 56 patients were enrolled, all patients had no distant metastasis confirmed by laparoscopic exploration and ascitic fluid cytology. The median age was 58 years; all patients were pMMR. In the efficacy analysis population (n=47), 41 patients completed 5–6 cycles and 6 patients completed 3–4 cycles of preoperative chemotherapy plus immunotherapy, no patients experienced disease progression leading to tumor metastasis during preoperative treatment. 47 patients underwent radical surgical resection, including 42 total gastrectomy, with an R0 resection rate of 98% (46/47). The prespecified primary endpoint of TRG 0/1 was achieved in 32% of patients (15/47; 95% CI, 21%–48%). Notably, 17% (n = 8) achieved pCR (ypT0N0), and 53% (n =25) were ypN0. Pathological response (TRG 0/1) was significantly higher in Lauren intestinal/mixed versus diffuse types (53% vs. 21%; p < 0.05), while efficacy was comparable between PD-L1 CPS ≥5 and <5 (44% vs. 30%). Grade 3/4 treatment-related adverse events occurred in 32% of patients (n=18), mainly thrombocytopenia and liver function impairment. Surgical morbidity (Clavien–Dindo grade II/III) occurred in 10.6% of surgical patients (5/47), including 1 patient with postoperative bleeding and 3 patients with anastomotic leakage; no perioperative mortality was observed. Conclusions: Total neoadjuvant tislelizumab plus chemotherapy demonstrated promising efficacy and an acceptable safety profile in patients with Borrmann-IV gastric cancer. Lauren classification may serve as a potential predictive biomarker and warrants further study. Clinical trial information: NCT06451211 .

The NEOSUMMIT-01 trial previously showed that adding the PD-1 antibody toripalimab to perioperative chemotherapy improved the pathologic response in patients with locally advanced gastric or gastroesophageal junction cancer. Here, we present the event-free survival (EFS) and overall survival (OS) after extended follow-up. A total of 108 patients were enrolled (toripalimab plus chemotherapy, n = 54; chemotherapy alone, n = 54). At the data cutoff date (August 29, 2025), the median follow-up was 43.2 months (interquartile range: 36.6-53.7). The 3-year EFS was 74.7% (95% CI, 63.6% to 87.7%) in the toripalimab plus chemotherapy group and 56.2% (95% CI, 43.3% to 73.0%) in the chemotherapy group, with a hazard ratio (HR) of 0.51 (95% CI, 0.27 to 0.98; P = .044). The 3-year OS was 81.3% (95% CI, 71.4% to 92.4%) versus 72.2% (95% CI, 61.2% to 85.2%), respectively, with an HR of 0.45 (95% CI, 0.21 to 0.95; P = .036). The survival benefits were consistent across most predefined subgroups and were maintained in the analysis excluding patients with dMMR. In conclusion, perioperative toripalimab plus chemotherapy significantly improved 3-year EFS and OS compared with chemotherapy alone, suggesting it as a promising treatment option for patients with locally advanced gastric or gastroesophageal junction cancer.

LBA4075 Background: Neoadjuvant chemoradiotherapy (CRT) has been proposed to improve tumor response over neoadjuvant chemotherapy (CT) in patients with locally advanced gastric cancer (LAGC). However, there are limited phase III clinical trials to confirm its survival benefit. Methods: The Neo-CRAG study is a multicenter phase III trial conducted in China. Patients with stage cT3N2/N3M0, cT4aN+M0, or cT4bNanyM0 gastric or esophagogastric junction (EGJ, Siewert type II/III) adenocarcinoma were randomly assigned (1:1) to the CRT or CT group. All patients received 3 cycles of preoperative XELOX, followed by D2 gastrectomy and adjuvant XELOX. In CRT group, radiotherapy (45Gy/25Fx) started after the first CT cycle, dose modifications were made with concurrent CRT (oxaliplatin: 130 to 100 mg/m²; capecitabine: 1000 to 825 mg/m²). The radiation target volume chiefly included moderate mucosal CTV expansion (3cm) beyond primary tumor (fasting state), and comprehensive elective regional lymph node irradiation (station 16a2 as the lower border). The primary endpoint was disease-free survival (DFS). The secondary endpoints were overall survival (OS), pathological complete response (pCR), R0 resection, and safety. Results: Between 2013-2022, 620 patients (310 per group) were enrolled from 13 referral hospitals, including 225 (36.3%) patients with EGJ primary. Median follow-up was 69.7 months (IQR, 49.6–97.4). The primary endpoint of DFS was met (HR 0.750, 95%CI 0.607-0.928; P=0.008). The 3-year DFS rate was 55.6% (95% CI, 50.1 - 61.1) in the CRT group and 42.4% (36.9 - 47.9) in the CT group, and median DFS was 52.7 months with CRT versus 24.4 months with CT. Meanwhile, the 5-year OS rate was 50.1% versus 44.2% (HR 0.781, 95% CI 0.628-0.970; P=0.025) and the median OS was 67.5 months with CRT compared to 37.6 months with CT. Subgroup analyses showed that the survival benefit of CRT over CT was consistent. 448 patients underwent D2 gastrectomy. pCR was achieved in 33/223 (14.8%) of patients in the CRT group and 14/225 (6.2%) in the CT group. ypN0 rates were 125/223 (56.1%) in the CRT group and 82/225 (36.4%) in the CT group. Tumor downstaging (ypT0-2) occurred in 95/223 (42.6%) of CRT group and 53/225 (23.6%) of CT group. In patients who underwent R0 resection, lower locoregional recurrence rate was observed in the CRT group (20/213, 9.4%), compared with the CT group (38/208, 18.3%). The safety population comprised 603 patients. Grade 3+ hematologic toxicity was relatively higher in the CRT group (44/302 [14.6%] vs 31/301 [10.3%]). Grade 3+ postoperative complication rates were comparable (20/223 [9.0%] vs 17/225 [7.6%]). Conclusion: For patients with LAGC, intensifying perioperative CT with preoperative radiotherapy improves survival and is an effective strategy for high-risk cases in need of enhanced locoregional control. Clinical trial information: NCT01815853 .

Table S1. NRAS mutations in leukemia

Inhalable particulate matter (PM) has emerged as a critical yet underappreciated carcinogenic factor in lung cancer, especially affecting non-smokers and populations residing in heavily polluted regions. Epidemiological research has confirmed the link between PM exposure and lung cancer risk, but the underlying biological pathways and clinical relevance are still not well understood. Here, we provide a comprehensive synthesis of current advances in PM-associated lung carcinogenesis, from population-level risk patterns to molecular pathogenesis and translational strategies. We outline the epidemiological burden and unique clinical features of PM-related lung cancer. We then propose a "Hallmarks of PM-associated lung cancer" framework, summarizing 12 features of how lung cancer evolves under PM exposure. This involves a complex interplay of cell-intrinsic oncogenic traits induced by PM (genetic alterations, epigenetic reprogramming, metabolic remodeling, stemness) and microenvironment reshaped by PM (inflammatory responses, immune suppression, angiogenesis, and pre-metastatic niche formation). Moreover, we critically examine the technical challenges in mechanistic studies and propose future solutions. Finally, we highlight urgent opportunities for integrating PM exposure into lung cancer screening, risk stratification, and prevention policies. This review offers a comprehensive framework for strategies to downsize the impact of air pollution on global lung health.

Abstract Purpose Neoadjuvant treatment (NAT) has become the standard treatment for locally advanced gastric cancer (LAGC). A small number of patients could achieve pathological complete response (pCR) after NAT. This study was performed to determine the factors predicting pCR and recurrence, and to investigate the pattern of recurrence in patients with pCR after NAT followed by surgery. Methods We collected 488 LAGC patients who underwent surgery in three hospitals between September 2015 and October 2022. The primary endpoint was overall survival (OS) and recurrence-free survival (RFS). Logistic regression analyses were performed to identify independent variables associated with pCR and the nomogram was created. Result Eighty (16.4%) patients were found with pCR and had significantly better OS and RFS than non-pCR group. The recurrence rates in the pCR and non-pCR groups were 7.5% (6 of 80) and 40.2% (164 of 408) respectively. However, the recurrence time and location had no significant difference between these two groups. Interestingly, all the 6 pCR patients who had recurrences received adjuvant therapy. Chemotherapy combined with immunotherapy as NAT significantly increased the pCR rate, but did not prolong RFS or OS compared to chemotherapy alone. Moreover, there was no significant difference in both OS and RFS between patients who received adjuvant chemotherapy and those who were observed only. Histological type and NAT regimen were independent factors to predict pCR in the nomogram. Conclusion Patients with pCR had a lower recurrence rate and better prognosis than the non-pCR group. Patients receiving chemo-immunotherapy as NAT had a higher pCR rate than those receiving chemotherapy alone, but this did not translate into significant improvement in long-term survival.

282 Background: The NEOSUMMIT-01 trial evaluated the efficacy of adding the PD-1 antibody toripalimab to perioperative chemotherapy in patients with locally advanced, resectable gastric or gastroesophageal junction (GEJ) cancer. Previously, we reported significant improvements in pathological complete or moderate regression (TRG 0/1) rate (44.4% vs 20.4%, P =0.009) and pathological complete response (pCR) rate (22.2% vs 7.4%, P =0.030) with the addition of toripalimab (2023 ASCO Abstract 4001; Nature Medicine 2024). Here, we present the 3-year survival outcomes after extended follow-up. Methods: In this open-label, randomized, phase 2 trial, patients with resectable gastric or GEJ cancer (clinical stage cT3–4a N+ M0) were randomized (1:1) to receive either three preoperative and five postoperative cycles of SOX/XELOX chemotherapy (chemotherapy group), or the same chemotherapy combined with toripalimab, followed by toripalimab monotherapy for 6 months (toripalimab plus chemotherapy group). The primary endpoint was pathological complete or moderate regression rate (TRG 0/1). Secondary endpoints included pathological complete response (pCR), R0 resection rate, objective response rate, disease control rate, event-free survival (EFS), overall survival (OS), and treatment safety. This analysis focuses on 3-year EFS and OS, assessed in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT04250948). Results: Between October 12, 2019, and June 27, 2022, 108 patients were enrolled (toripalimab plus chemotherapy, n = 54; chemotherapy alone, n = 54) and included in the intention-to-treat analysis. As of the clinical cutoff date (August 29, 2025), the median follow-up was 43.2 months (IQR 36.6–53.7). The 3-year EFS was 74.7% (95% CI: 63.6–87.7%) in the toripalimab plus chemotherapy group and 56.2% (95% CI: 43.3–73.0%) in the chemotherapy group, with a hazard ratio (HR) of 0.52 (95% CI: 0.27–1.00; P = 0.047). The 3-year OS was 81.3% (95% CI: 71.4–92.4%) versus 72.2% (95% CI: 61.2–85.2%), respectively, with an HR of 0.45 (95% CI: 0.21–0.95; P = 0.031). Conclusions: Perioperative toripalimab combined with chemotherapy demonstrated significantly improved 3-year EFS and OS compared to chemotherapy alone, suggesting it as a promising treatment option for patients with locally advanced, resectable gastric or GEJ adenocarcinoma. Clinical trial information: NCT04250948 .

BACKGROUND:Adjuvant chemotherapy following D2 gastrectomy constitutes the standard-of-care for resectable gastric or gastroesophageal junction (GEJ) carcinoma. The CAPITAL trial is a multicenter, randomized, phase 3 study, aiming to assess the efficacy and safety of adjuvant oxaliplatin plus S-1 (SOX) versus S-1 alone. METHODS:Patients with histologically confirmed pathological stage II-III gastric or GEJ adenocarcinoma after gastrectomy with D2 lymphadenectomy were randomly assigned (1:1) to receive either the SOX regimen (n = 362) or the S-1 regimen (n = 362). The primary endpoint was overall survival. This study is registered with ClinicalTrials.gov (NCT01795027). FINDINGS:The median follow-up was 74.0 months (interquartile range [IQR], 35.5-89.3). The 5-year overall survival rates were 70.9% (95% confidence interval [CI], 66.0-76.1) in the SOX group and 62.9% (95% CI, 57.8-68.5) in the S-1 group (hazard ratio [HR], 0.74; 95% CI, 0.58-0.95; p = 0.018). The 3- and 5-year disease-free survival rates were 71.2% (95% CI, 66.5-76.3) and 66.2% (95% CI, 61.2-71.6) in the SOX group, as compared with 65.1% (95% CI, 60.2-70.5) and 55.6% (95% CI, 50.4-61.3) in the S-1 group (HR, 0.76; 95% CI, 0.61-0.96). Treatment-related adverse events of grade 3-4 occurred in 87 (25%) of 349 patients in the SOX group and 45 (13%) of 347 patients in the S-1 group. The most common grade 3-4 adverse event was neutropenia, occurring in 44 (13%) of 349 patients in the SOX group and 23 (7%) of 347 patients in the S-1 group. CONCLUSIONS:The addition of adjuvant oxaliplatin to S-1 chemotherapy significantly improved overall survival and disease-free survival in patients with gastric cancer. FUNDING:This research was supported by the National Natural Science Foundation of China (82573092 and 82573387).

In the original publication [...].

4080 Background: The use of Disitamab vedotin (RC48) and programmed death-1 (PD-1) inhibitor is effective in patients with HER2-expressing advanced gastric or gastroesophageal junction (G/GEJ) cancer. However, their use has not been investigated in patients with localized disease. This trial evaluated the safety and anti-tumor activity of perioperative chemotherapy combined with RC48 and toripalimab in the treatment of locally advanced HER2-overexpressed (defined as IHC 2+ or 3+) G/GEJ cancer. Methods: This study was an investigator-initiated, open-label, single-arm, phase 2 trial was conducted at Sun Yat-sen University Cancer Center. Eligible patients with HER2-overexpressed locally advanced G/GEJ cancer received 3-4 cycles of neoadjuvant XELOX plus RC48 and toripalimab, followed by surgery. The primary endpoint was TRG 0/1 after neoadjuvant treatment. This study is registered at Chinese Clinical Trial Registry (ChiCTR2400081677). Results: Between July 11, 2024, and July 11, 2025, of 26 patients screened for eligibility, 25 patients were enrolled, all patients had no distant metastasis confirmed by laparoscopic exploration and ascitic fluid cytology, 20 (80%) patients had clinical stage III disease and 5(20%) with stage II. Of these 25 patients, the median age was 58 (IQR, 37-74) years. Tumors were located in the stomach in 21(84%) patients and in the gastroesophageal junction in 4 (16%) patients. The patients with HER2 IHC expression of 2+ and 3+ was 21 (84%) and 4 (16%) respectively. 15 (60%) patients had the PD-L1 CPS of 1 or more, 24 (96%) patients were pMMR. The primary endpoint of TRG 0/1 was met in 16 (64%) patients, 9 (36%) patients achieved pCR (ypT0N0), and 24 (96%) were ypN0. 10 (40%) patients experienced grade 3 treatment-related adverse events, the most common treatment-related adverse events were increased ALT or AST (5 [20%] patients) and neutropenia (3 [12%] patients), no grade 4 treatment-related adverse events. Surgical morbidity (Clavien-Dindo II/III) occurred in 2 of 25 (8%) patients, with no 30-day surgical mortality. Conclusions: Our findings suggested that perioperative chemotherapy plus RC48 and toripalimab had controllable safety and showed encouraging efficacy in patients with HER2-overexpressed G/GEJ cancer. Clinical trial information: ChiCTR2400081677.

289 Background: In Asia, adjuvant S-1 monotherapy following D2 gastrectomy represents a standard treatment for patients with pathological stage II/III gastric or gastro-oesophageal junction (GEJ) carcinoma. We aimed to assess the efficacy and safety of adjuvant oxaliplatin plus S-1 versus S-1 administered in this setting. Methods: The CAPITAL trial was a multicentre, randomised, open-label, phase 3 study conducted at 13 hospitals in China. Eligible patients were aged 18 years or older with histologically confirmed pathological stage II-III gastric or GEJ adenocarcinoma after gastrectomy with D2 lymph node dissection, with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2. Patients were randomly assigned (1:1) to receive SOX regimen (6 cycles of S-1 40-60 mg orally twice daily for 2 weeks in each 3-week cycle and oxaliplatin 100 mg/m 2 administered intravenously once every 3 weeks, followed by 10 additional cycles of S-1), or S-1 regimen (16 cycles of S-1 at a dose of 40-60 mg twice per day for 2 weeks, followed by a rest of 1 week). The primary endpoint was overall survival in the intention-to-treat population. Safety analysis were done in patients who received at least one dose of the trial drug. This study is registered with ClinicalTrials.gov, NCT01795027. Results: Between Oct 28, 2011 and Nov 3, 2017, 724 patients were randomly assigned to receive either adjuvant SOX (n=362) or adjuvant S-1 (n=362). By the clinical cutoff date of Nov 3, 2022, the median follow-up time was 74.0 months (IQR 35.5-89.3). The 5-year overall survival were 70.9% (95% CI 66.0-76.1) in the SOX group and 62.9% (57.8-68.5) in the S-1 group. The HR for death in the SOX group, as compared with the S-1 group, was 0.74 (0.58-0.95; p=0.018). The 3 and 5-year disease-free survival were 71.2% (66.5-76.3) and 66.2% (61.2-71.6) in the SOX group, as compared with 65.1% (60.2-70.5) and 55.6% (50.4-61.3) in the S-1 group. The HR of disease-free survival for the SOX group versus the S-1 group was 0.76 (0.61-0.96; p=0.021). Treatment-related adverse events of any grade occurred in 295 (85%) of 349 patients in the SOX group and 260 (75%) of 347 patients in the S-1 group. The most common grade 3-4 adverse events was neutropenia (44 (13%) of 349 patients in the SOX group and 23 (7%) of 347 patients in the S-1 group). No treatment-related deaths were recorded. Conclusions: The addition of oxaliplatin to S-1 chemotherapy significantly improved both overall survival and disease-free survival in patients with stage II-III gastric or GEJ adenocarcinoma. SOX regimen should be considered as a standard adjuvant treatment option for this patient population following D2 gastrectomy. Clinical trial information: NCT01795027 .

Abstract RAS mutations are prevalent in leukemia, including mutations at G12, G13, T58, Q61, K117, and A146. These mutations are often crucial for tumor initiation, maintenance, and recurrence. Although much is known about RAS function in the last 40 years, a substantial knowledge gap remains in understanding the mutation-specific biological activities of RAS in cancer and the approaches needed to target specific RAS mutants effectively. The recent approval of KRASG12C inhibitors, adagrasib and sotorasib, has validated KRAS as a direct therapeutic target and demonstrated the feasibility of selectively targeting specific RAS mutants. Nevertheless, KRASG12C remains the only RAS mutant successfully targeted with FDA-approved inhibitors for cancer treatment in patients, limiting its applicability for other oncogenic RAS mutants, such as G12D, in leukemia. Despite these challenges, new approaches have generated optimism about targeting specific RAS mutations in an allele-dependent manner for cancer therapy, supported by compelling biochemical and structural evidence, which inspires further exploration of RAS allele-specific vulnerabilities. This review will discuss the recent advances and challenges in the development of therapies targeting RAS signaling, highlight emerging therapeutic strategies, and emphasize the importance of allele-specific approaches for leukemia treatment.

Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are generally resistant to targeted therapy with tyrosine kinase inhibitors (TKIs), such as imatinib, and there are no standard therapeutic options for advanced SDH-deficient GISTs. The precise oncogenic mechanisms of SDH mutations in GIST have not been elucidated. Olverembatinib, a novel multikinase inhibitor, has shown promising activity in treating imatinib-resistant GIST. We conducted a phase 1 study (NCT03594422) to evaluate the safety and antitumor activity of olverembatinib in 66 patients with unresectable/metastatic GIST/other solid tumors, including 26 with TKI-failed SDH-deficient GISTs. To our knowledge, this is the largest prospective clinical trial for this rare GIST subtype. The median follow-up was 14.5 (0.9–57.5) months. Olverembatinib was well tolerated; treatment-emergent adverse events (≥20%) included increases in hepatic transaminases, increases in leukocytes and neutrophils, anemia, and pyrexia. For SDH-deficient GISTs, confirmed partial responses were observed in 6 of the 26 evaluable patients (objective response rate, 23.1%; 95% CI, 9–43.7); an additional 16 (61.5%) did not progress during the first 6 months of treatment. This resulted in a clinical benefit rate of 84.6% (95% CI, 65.1–95.6), and the median progression-free survival was 25.7 months (95% CI, 12.9–NR). As a putative mechanism of action, translational research revealed significant lipid enrichment with the overexpression of lipid uptake-related genes and proteins, including CD36, fatty acid binding proteins, fatty acid transport proteins, and lipid metabolites, in SDH-deficient GIST patients, and olverembatinib suppressed lipid uptake and CD36 expression in GIST cells. Olverembatinib also exerts antitumor effects by inhibiting tumorigenic signaling pathways associated with hypoxia, angiogenesis, proliferation, and survival.

The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role in tumorigenesis and cancer progression. However, the detailed biological functions and underlying mechanisms of m6A regulation in gastric cancer (GC) are poorly understood. Our research revealed that the m6A demethylase ALKBH5 was markedly downregulated in GC tissues, which was associated with poor patient prognosis. Functional studies demonstrated that suppressing ALKBH5 expression enhanced GC cell proliferation, migration, and invasion. Mechanistically, ALKBH5 removed m6A modifications from the 5’ uncapped and polyadenylated transcripts (UPTs) of WRAP53. This demethylation decreased WRAP53 stability and translation efficiency. The lower level of WRAP53 disrupts the interaction between USP6 and RALBP1 protein, promoting RALBP1 degradation and thereby suppressing the PI3K/Akt/mTOR signaling cascade, ultimately attenuating the progression of GC. These findings highlight the pivotal role of ALKBH5-mediated m6A demethylation in inhibiting GC progression and the potential role of ALKBH5 as a promising biomarker and therapeutic target for GC intervention.

Artificial intelligence (AI) is significantly advancing precision medicine, particularly in the fields of immunogenomics, radiomics, and pathomics. In immunogenomics, AI can process vast amounts of genomic and multi-omic data to identify biomarkers associated with immunotherapy responses and disease prognosis, thus providing strong support for personalized treatments. In radiomics, AI can analyze high-dimensional features from computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT) images to discover imaging biomarkers associated with tumor heterogeneity, treatment response, and disease progression, thereby enabling non-invasive, real-time assessments for personalized therapy. Pathomics leverages AI for deep analysis of digital pathology images, and can uncover subtle changes in tissue microenvironments, cellular characteristics, and morphological features, and offer unique insights into immunotherapy response prediction and biomarker discovery. These AI-driven technologies not only enhance the speed, accuracy, and robustness of biomarker discovery but also significantly improve the precision, personalization, and effectiveness of clinical treatments, and are driving a shift from empirical to precision medicine. Despite challenges such as data quality, model interpretability, integration of multi-modal data, and privacy protection, the ongoing advancements in AI, coupled with interdisciplinary collaboration, are poised to further enhance AI’s roles in biomarker discovery and immunotherapy response prediction. These improvements are expected to lead to more accurate, personalized treatment strategies and ultimately better patient outcomes, marking a significant step forward in the evolution of precision medicine.