BRAF V600E + KRAS G12D

These modifications altered the response to TKI treatment both in vitro and in vivo. Overall, these models serve as valuable tools for studying the biology of NTRK fusion tumors, their treatment response in a treatment-naïve or -experienced state, and the mechanisms underlying treatment resistance.

These data support that the tumor likely arose from three separate clonal populations, the BRAF V600E population and the KRAS G12G and KRAS G12C populations, each having distinct molecular pathways to tumorigenesis. Future directions include measuring spatial gene expression patterns of the tumor to correlate with the tumor mapping described above and to further characterize the multiple populations of tumor cells harboring different driver alterations and molecular pathways to tumorigenesis.

Our findings indicate that dual-driver mutations occur in a rare subset of CRC, often within the same tumor cells and across multiple tumor sites. Their presence and a lower rate of allelic imbalance may be related to dose-dependent signaling within the mitogen-activated protein kinase pathway.

Moreover, validation of tissue and plasma samples obtained from melanoma, colorectal, and lung cancer patients showed excellent agreement with Sanger sequencing and ddPCR; remarkably, the efficiency of this AS-PCR/acoustic methodology to detect mutations in real samples was demonstrated to be below 1% MAF. The combined high sensitivity and technology-readiness level of the methodology, together with the ability for multiple sample analysis (24 array biochip), cost-effectiveness, and compatibility with routine workflow, make this approach a promising tool for implementation in clinical oncology labs for tissue and liquid biopsy.

We sought to investigate mechanisms of acquired resistance to FGFRi and approaches to overcome resistance. Longitudinal plasma samples were collected from patients with FGFR pathway alterations enrolled in the futibatinib phase I trial (NCT02052778) and sequenced using a targeted, 73-gene panel... Convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi therapy. Work is ongoing to determine if targeting co-alterations may enhance the efficacy of FGFRi in FGFR2-fusion driven malignancies.