Biology subjects

Ranieri, M.

Publications and source records attributed to Ranieri, M..

3 recordsLinked to original sources

bioRxiv2026

Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRASG12C suppresses PI3Kα and leads to potent tumor inhibition

Current approved KRASG12C inhibitors covalently bind the inactive GDP-bound (OFF) form of KRASG12C. Recently, KRASG12C inhibitors that selectively bind to the GTP-bound (ON) form of both KRASG12C (ON) and (OFF) forms have been reported and entered clinical testing. In principle, KRASG12C (ON) inhibitors may be less susceptible to adaptive mechanisms that promote resistance to (OFF) inhibitors, however the specific mechanisms that differentiate the activity of (ON) versus (OFF) inhibition are not well understood. We profiled the activity of BBO-8520, a covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C, in KRASG12C-mutant non-small cell lung cancer models. BBO-8520 exerted more potent and sustained inhibition of KRASG12C and anti-tumor activity in vitro and in vivo compared with sotorasib, a KRASG12C (OFF)-only inhibitor. While cells treated with BBO-8520 or sotorasib both exhibited feedback reactivation of MAPK signaling driven by wild-type HRAS/NRAS isoforms, more durable suppression of KRASG12C by BBO-8520 was associated with decreased PI3K-AKT activation in vitro. Disruption of the interaction between RAS and PI3K using a novel protein:protein interaction inhibitor suppressed PI3K-AKT activation and increased the tumor response to sotorasib to a similar level as BBO-8520. Moreover, in some contexts, disruption of RAS-PI3K further increased the anti-tumor activity of BBO-8520 monotherapy. These results reveal mechanistic differences between KRAS (ON) and (OFF) inhibitors, highlight the importance of PI3K-AKT signaling in driving resistance to KRAS inhibition in lung cancer, and suggest combination strategies that suppress PI3K-AKT to improve the response to KRAS inhibitors.

cancer biology↗

bioRxiv2025

Deep Mutational Scanning Reveals EGFR Mutations Conferring Resistance to the 4th-generation EGFR tyrosine kinase inhibitor BLU-945

IntroductionOsimertinib, a covalent third-generation EGFR tyrosine kinase inhibitor (TKI) is the first-line standard of care for EGFR L858R and ex19del lung adenocarcinoma; however, tumors frequently acquire resistance through second-site mutations. Fourth-generation inhibitors designed to overcome common second-site resistance liabilities are in clinical development. MethodsWe performed deep mutational scanning (DMS) of the EGFR kinase domain in the context of an EGFR L858R driver mutation by transducing Ba/F3 cells with a saturation library of [~]17,000 EGFR L858R kinase domain variants. Ba/F3 cells expressing the DMS library were exposed to either osimertinib or BLU-945 to select for escape mutations. ResultsL718X mutations were enriched across all conditions as well as mutations private to BLU-945 treated samples including K714R, K716T, L718V, T725M, K728E, K754E/N, N771S/T, T783I, Q791L/K, G863S, S895N, K929I, and M971L. In silico pairwise comparisons of resistance profiles between each single agent condition suggested that combination treatment with osimertinib and BLU-945 would effectively suppress orthogonal resistance mechanisms, apart from L718X. A secondary DMS screen with osimertinib and BLU-945 in combination exclusively enriched for L718X mutations. L718X mutations were present in two patients treated with BLU-945 at our institution. One patient with both EGFR L858R and L718Q mutations prior to treatment was noted to have early progression. A second patient with EGFR L858R, T790M, and C797S at the time of enrollment acquired an L718V mutation at progression. ConclusionsThis study underscores the utility of comprehensive resistance profiles of single compounds, which can be used to predict the emergence of clinical resistance mutations and to devise combination treatments designed to suppress clonal escape.

cancer biology↗

bioRxiv2023

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1-mutant lung cancer

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD+ degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD+. Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)--key downstream effectors of LKB1-- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCELoss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

cancer biology↗