Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m⁶A), is involved in the tumorigenesis of many types of cancer. As one of the largest m⁶A methyltransferase complex components, KIAA1429 bridges the catalytic m⁶A methyltransferase components, such as METTL3. In gastric cancer, KIAA1429 was reported to promote cell proliferation. However, whether KIAA1429 is involved in the resistance of gastric cancer to cisplatin remains unclear. Here, we generated cisplatin resistant gastric cancer cell lines, and compared the m⁶A content between resistant cells and wild type cells. The m⁶A content as well as KIAA1429 expression are higher in resistant cells. Interestingly, the expression of KIAA1429 was significantly increased after cisplatin treatment. We then used shRNA to knockdown KIAA1429 and found that resistant cells responded more to cisplatin treatment after KIAA1429 depletion, while overexpression of KIAA1429 decreased the sensitivity. Moreover, we identified a putative p65 binding site on the promoter area of KIAA1429 and ChIP assay confirmed the binding. p65 depletion decreased the expression of KIAA1429. YTHDF1 is the most abundant m⁶A “reader” that interacts with m⁶A modified mRNA. Mechanistically, YTHDF1 was recruited to the 3′-untranslated Region (3′-UTR) of transcriptional factor, FOXM1 by KIAA1429 and stabilized FOXM1 mRNA. More importantly, KIAA1429 knockdown increased the sensitivity of resistant cells to cisplatin in vivo. In conclusion, our results demonstrated that KIAA1429 facilitated cisplatin resistance by stabilizing FOXM1 mRNA in gastric cancer cells.

The Fanconi anemia (FA) pathway is essential for repairing DNA interstrand crosslinks (ICL). ICLs induce stalled DNA replication forks and trigger activation of the FA pathway by promoting recruitment of the FANCM/FAAP24/MHF complex to ICL sites. Given that stalled replication forks are proximal to ICL sites, fork-associated proteins may coordinate with FA factors to rapidly sense ICLs for activation of FA signaling. Here we report that And-1, a replisome protein, is critical for activation of the FA pathway by sensing ICL-stalled forks and recruiting the FANCM/FAAP24 complex to ICLs. In response to ICLs, And-1 rapidly accumulated at ICL-stalled forks in a manner dependent on ataxia telangiectasia and Rad3-related protein–induced phosphorylation at T826. And-1 phosphorylation triggered an intramolecular change that promoted the interaction of And-1 with FANCM/FAAP24, resulting in recruitment of the FANCM/FAAP24 complex to ICLs. Furthermore, p-T826 And-1 was elevated in cisplatin-resistant ovarian cancer cells, and activated And-1 contributed to cisplatin resistance. Collectively, these studies elucidate a mechanism by which And-1 regulates FA signaling and identify And-1 as a potential target for developing therapeutic approaches to treat platinum-resistant ovarian cancer. Significance: This work shows that phosphorylation of And-1 by ATR activates Fanconi anemia signaling at interstrand crosslink–stalled replication forks by recruiting the FANCM/FAAP24 complex, revealing And-1 as a potential therapeutic target in cancer.

Research probing the clinical utility of immune checkpoint inhibitors (ICIs) supports the development of novel, efficacious approaches to treating colorectal cancer (CRC) patients without chemotherapy. Therapeutic innovations, however, need to be evaluated in light of real-world economic considerations. This study compared the cost-effectiveness of first-line dual-immunotherapies, single immunotherapy, and chemotherapies in the treatment of microsatellite-instability-high/mismatch repair deficient (MSI-H/dMMR) advanced CRC from the perspective of American healthcare systems. Individual patient data (IPD) from the KEYNOTE-177 and CheckMate-8HW trials were collected with IPDfromKM and used to develop a Markov model with a 30-year duration and three mutually exclusive health states, providing a framework for the evaluation of the cost-effectiveness of first-line nivolumab together with ipilimumab, pembrolizumab, and chemotherapy for treating MSI-H/dMMR advanced CRC. Primary outcomes consisted of total costs, life years (LYs), quality-adjusted LYs (QALYs), incremental cost-effectiveness ratio (ICER) values, and incremental net-health benefits (INHB) at willingness-to-pay (WTP) thresholds of $100,000/QALY in the USA. Nivolumab plus ipilimumab ($482,416 [18.72 QALYs]) and pembrolizumab ($336,617 [12.21 QALYs]) increased cost (effectiveness) by $145,800 (5.30 QALYs) than chemotherapy ($374,728 [10.07 QALYs]), respectively. The corresponding ICER was $13,670/QALY and -$14,768/QALY, with INHB of 2.52 and 6.80 QALYs, respectively. It was further found that the ICER and INHB of nivolumab plus ipilimumab versus pembrolizumab were $22,386/QALY and 3.84 QALYs, respectively. In addition, the established model is stable. First-line immunotherapeutic treatments for MSI-H/dMMR advanced CRC cases in the USA appears to be cost-effective, with a dual-immunotherapeutic regimen consisting of nivolumab plus ipilimumab being preferable.

The Fanconi anemia (FA) pathway is essential for repairing DNA interstrand crosslinks (ICL). ICLs induce stalled DNA replication forks and trigger activation of the FA pathway by promoting recruitment of the FANCM/FAAP24/MHF complex to ICL sites. Given that stalled replication forks are proximal to ICL sites, fork-associated proteins may coordinate with FA factors to rapidly sense ICLs for activation of FA signaling. Here we report that And-1, a replisome protein, is critical for activation of the FA pathway by sensing ICL-stalled forks and recruiting the FANCM/FAAP24 complex to ICLs. In response to ICLs, And-1 rapidly accumulated at ICL-stalled forks in a manner dependent on ataxia telangiectasia and Rad3-related protein–induced phosphorylation at T826. And-1 phosphorylation triggered an intramolecular change that promoted the interaction of And-1 with FANCM/FAAP24, resulting in recruitment of the FANCM/FAAP24 complex to ICLs. Furthermore, p-T826 And-1 was elevated in cisplatin-resistant ovarian cancer cells, and activated And-1 contributed to cisplatin resistance. Collectively, these studies elucidate a mechanism by which And-1 regulates FA signaling and identify And-1 as a potential target for developing therapeutic approaches to treat platinum-resistant ovarian cancer.Significance:This work shows that phosphorylation of And-1 by ATR activates Fanconi anemia signaling at interstrand crosslink–stalled replication forks by recruiting the FANCM/FAAP24 complex, revealing And-1 as a potential therapeutic target in cancer.

Supplementary Data from And-1 Coordinates with the FANCM Complex to Regulate Fanconi Anemia Signaling and Cisplatin Resistance

With the increasing incidence of colorectal cancer, understanding different subgroups, such as the microsatellite stable (MSS) population, is crucial. Our study aimed to explore the unique characteristics and underlying genetic and epigenetic features of the microsatellite stable (MSS) population within colorectal cancer. Using 325 samples, we compared MSS with other microsatellite statuses on more than 50 clinical indicators. A significantly different overall gene mutation rate was observed in the MSS group compared to the other groups, especially in P53 mutations. No notable changes were found in epigenetics. The results suggest that MSS colorectal cancer cases are more likely to have gene mutations than other subgroups. We also found that the N stage was lower in the MSI-H group. These findings provide crucial insights that can guide future drug development and treatment plans for the MSS population.