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Maintenance of p-eIF2alpha levels by the eIF2B complex is vital for colorectal cancer

ABSTRACT: Protein synthesis is an essential process, deregulated in multiple tumor types showing differential dependence on translation factors compared to untransformed tissue. We show that colorectal cancer (CRC) with loss-of-function mutation in the APC tumor suppressor depends on an oncogenic translation program regulated by the ability to sense phosphorylated eIF2a (p-eIF2a). Despite increased protein synthesis rates following APC loss, eIF2a phosphorylation, typically associated with translation inhibition, is enhanced in CRC. Elevated p-eIF2a, and its proper sensing by the decameric eIF2B complex, are essential to balance translation. Knockdown or mutation of eIF2Ba and eIF2Bd, two eIF2B subunits responsible for sensing p-eIF2a, impairs CRC viability, demonstrating that the eIF2B/p-eIF2a nexus is vital for CRC. Specifically, the decameric eIF2B linked by two eIF2Ba subunits is critical for translating growth-promoting mRNAs which are induced upon APC loss. Depletion of eIF2Ba in APC-deficient murine and patient-derived organoids establishes a therapeutic window, validating eIF2Ba as a target for clinical intervention. In conclusion, we demonstrate how expression of the oncogenic signature in CRC is crucially controlled at the translational level.

SUBMITTER: Ivana Paskov Skapik

PROVIDER: S-SCDT-10_1038-S44318-025-00381-9 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:ImportanceUnregulated drug prices increase cancer therapy costs. After induction chemotherapy, patients with metastatic colon cancer can receive maintenance capecitabine and bevacizumab therapy based on improved progression-free survival, but whether this treatment's cost justifies its benefits has not been evaluated in the United States.ObjectiveThis study sought to determine the influence of capecitabine and bevacizumab drug prices on cost-effectiveness from a Medicare payer's perspective.Design, setting, and participantsThe incremental cost-effectiveness of capecitabine and bevacizumab maintenance therapy was determined with a Markov model using a quality-of-life penalty based on outcomes data from the CAIRO phase 3 randomized clinical trial (RCT), which included 558 adults in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. The outcomes were modeled using Markov chains to account for patients who had treatment complications or cancer progression. Transition probabilities between patient states were determined, and each state's costs were determined using US Medicare data on payments for capecitabine and bevacizumab treatment. Deterministic and probabilistic sensitivity analyses identified factors affecting cost-effectiveness.Main outcomes and measuresLife-years gained were adjusted using CAIRO3 RCT quality-of-life data to determine quality-adjusted life-years (QALYs). The primary end point was the incremental cost-effectiveness ratio, representing incremental costs per QALY gained using a capecitabine and bevacizumab maintenance regimen compared with observation alone.ResultsMarkov model estimated survival and complication outcomes closely matched those reported in the CAIRO3 RCT, which included 558 adults (n = 197 women, n = 361 men; median age, 64 and 63 years for patients in the observation and maintenance therapy groups, respectively) in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. Incremental costs for a 3-week maintenance chemotherapy cycle were $6601 per patient. After 29 model iterations corresponding to 60 months of follow-up, mean per-patient costs were $105 239 for maintenance therapy and $21.10 for observation. Mean QALYs accrued were 1.34 for maintenance therapy and 1.20 for observation. The incremental cost-effectiveness ratio favored maintenance treatment, at an incremental cost of $725 601 per QALY. The unadjusted ratio was $438 394 per life-year. Sensitivity analyses revealed that cost-effectiveness varied with changes in drug costs. To achieve an incremental cost-effectiveness ratio of less than $59 039 (median US household income) per unadjusted life-year would require capecitabine and bevacizumab drug costs to be reduced from $6173 (current cost) to $452 per 3-week chemotherapy cycle.Conclusions and relevanceAntineoplastic therapy is expensive for payers and society. The price of capecitabine and bevacizumab maintenance therapy would need to be reduced by 93% to make it cost-effective, a finding useful for policy decision making and payment negotiations.

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Maintenance of p-eIF2alpha levels by the eIF2B complex is vital for colorectal cancer

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