KRAS G12

P1, N=52, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2030 --> Dec 2026

P1, N=681, Recruiting, Astellas Pharma Inc | Trial completion date: Dec 2027 --> Dec 2028 | Trial primary completion date: Dec 2027 --> Dec 2028

P3, N=400, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting

The patient underwent radical local wide resection 1 month later, and no recurrence or metastasis was observed during a follow-up period of 12 months. The present case report provides a real-world reference for the clinical diagnosis, selection of treatment plans and evaluation of the prognosis of painless PMA.

After carboplatin and paclitaxel treatment, a combination chemotherapy used in human LUSC, we detected increased neutrophils in circulation, spleen and tumors, and increased Bcl-xL in neutrophils and TANs. Bcl-xL blockade decreased the pool of Bcl-xL-high TANs and synergized with chemotherapy. Altogether, our results suggest distinct outcomes for targeting TANs in different tumor types and reinforce the concept of repurposing BH3 mimetics against cancer.

Mechanistically, loss of NSUN2 reduces ERK phosphorylation in Apc-deficient models, and oncogenic KrasG12D expression is sufficient to restore ERK signalling and rescue ISC expansion. Together, this establishes a novel role for NSUN2 as a key regulator of ISC-driven CRC initiation and describes a critical molecular mechanism linking m5C methylation to MAPK-driven stem cell transformation.

In addition, we identified previously undescribed cryptic pockets and validated select hits using computational chemistry and NMR spectroscopy. These pockets represent promising opportunities for future drug discovery campaigns.

An experimental PROTAC drug designed to degrade mutant KRASG12D produced tumor responses in patients with advanced non-small cell lung cancer and pancreatic ductal adenocarcinoma in a phase I trial, with limited toxicity. Investigators are now testing the therapy in combination regimens and later-stage studies as competition intensifies among companies developing drugs against the common cancer driver.

An example of this is blinatumomab, an FDA-approved BiTE structure for the treatment of B-cell acute lymphoblastic leukemia (B-ALL)...Ultimately, we present two promising TCR-BiTEs that are specific to two different HLAs (HLA:03:01 and HLA:11:01) targeting KRAS G12V, serving as valuable starting points for further evaluation and design in vitro. We validated the design of our TCR-BiTE structures through AlphaFold tools, free energy estimation methods, and molecular dynamics analysis, thereby also providing a potential computational pipeline that can be applied in the design of TCR-BiTE structures targeting other mutations in addition to KRAS G12V.

This case highlights the potential of sotorasib in combination regimens as a first-line treatment strategy for KRAS G12C-mutated NSCLC and underscores the importance of individualized treatment planning. However, the use of sotorasib in the first-line setting remains an exploratory off-label approach and requires further clinical evidence to validate this treatment strategy.

A 58-year-old man with KRAS-G12C-mutated stage IVB lung adenocarcinoma initiated first-line treatment with carboplatin + pemetrexed + pembrolizumab...Intravenous methylprednisolone led to rapid defervescence and biochemical improvement...Thereafter, he initiated adagrasib, achieving a durable partial response. This case illustrates discordance between metabolic quiescence and later structural damage in immune checkpoint inhibitor-associated aortitis. This supports long-term structural surveillance, as 18F-FDG PET/CT normalization does not guarantee structural safety.

This study is the largest longitudinal analysis of KRASM testing conducted in Australia, with significant improvement in testing rates seen over the time period. Rates of KRASM and characteristics of Australian KRAS mt patients correspond with published literature.