Abstract C163: KRAS alterations combined with TP53 mutations as novel synthetic lethal genomic lesions for PKMYT1 inhibition
Bibliographic record
Abstract
Abstract Background: Membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase (PKMYT1) is a cell cycle regulatory kinase that inhibits CDK1/CyclinB activity, delaying entry into mitosis in tumor cells experiencing replication stress (RS). RS is frequently induced by genetic alterations that drive premature transition from G1 to S phase, promoting genome instability and creating a synthetic lethal (SL) relationship between these specific alterations and PKMYT1 inhibition. This relationship has been demonstrated preclinically and clinically with CCNE1 amplification and FBXW7 mutations, common alterations in ovarian and colorectal cancers, respectively. Oncogenic KRAS gain of function (GOF) mutations, combined with TP53 alterations, are bona fide drivers of RS. Here we investigate the relationship between KRAS/TP53 alterations and PKMYT1 inhibition, mediated by the first-in-class, potent and selective PKMYT1 inhibitor lunresertib (RP-6306), alone or in combination with RS-inducing agents. Methods: KRAS/TP53 double mutant isogenic cell pairs, across relevant tumor origins, were genetically engineered to express multiple KRAS GOF mutant codons and alleles (G12D, G12C, G12V, G12R, G13D and Q61H). Cell cycle distribution perturbations and RS were evaluated. Sensitivity to lunresertib alone or in combination with chemotherapeutic or targeted agents was assessed by cell growth assays. In vitro findings were further evaluated in KRAS/TP53 double mutant patient-derived xenografts (PDX). Results: Lunresertib inhibited the growth of isogenic KRAS/TP53 double mutant cells, with up to a 12-fold EC50 shift compared to control parental cells. Combination of lunresertib with RS-inducing chemotherapeutic agents (eg. gemcitabine), or the ATR inhibitor camonsertib (RP-3500) led to synergistic cell growth inhibition in KRAS/TP53 mutant cells at significantly lower concentrations than in wild type lines. Mechanistically, KRAS/TP53 isogenic cells showed elongated S-phase and increased cyclin B1 levels, phenocopying the effects of CCNE1 amplification. Lunresertib induced premature mitosis and DNA damage in KRAS/TP53 mutant cells, sparing parental cell lines. PDX efficacy studies demonstrated robust combination benefit in pancreatic, lung and colorectal settings, with durable tumor regressions and complete responses observed. Conclusion: GOF KRAS mutations, when combined with TP53 alterations, show a strong SL relationship with PKMYT1 inhibition, alone or in combination with RS-inducing antitumor agents. Importantly, the SL phenotype was observed across multiple tumor indications and KRAS mutant codons/alleles, suggesting a potential broad scope of clinical utility beyond approved KRAS inhibitors. The mechanism is similar to CCNE1 amplification, characterized by enhanced G1/S transition driving heightened dependence on PKMYT1 to inhibit CDK1/CyclinB. Taken together, our data form rationale for the therapeutic evaluation of PKMYT1 inhibitors in KRAS/TP53 altered tumors and uncover a potential new patient selection biomarker for lunresertib. Citation Format: Marc L. Hyer, Jimmy Fourtounis, David Gallo, Vivek Bhaskaran, Rino Stocco, Rosie Kryczka, Sai Save, Helen Burston, Olivier Nicolas, Stephen Morris, Anne Roulston, Jordan T. F. Young, Michal Zimmermann, C. Gary Marshall, Artur Veloso, Elia Aguado-Fraile. KRAS alterations combined with TP53 mutations as novel synthetic lethal genomic lesions for PKMYT1 inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C163.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".