byl719 and encorafenib

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Thiazoles

This was a cohort study on genetic alterations in patients with BRAF. In total, 37 patients were included in this cohort. Genetic alterations in EGFR and in PIK3CA are associated with non-response. A greater fraction of non-responders (75%) versus responders (46%) had at least one genetic alteration in other genes than TP53, APC or BRAF. Secondary resistance mutations (n = 16 patients) were observed most frequently in the PI3K pathway (n = 6) and in receptor tyrosine kinases (n = 4), leading to increased upstream signalling.. Genetic alterations in the PI3K and upstream receptor tyrosine kinases were mostly associated with intrinsic and acquired resistance. By understanding these alterations, simultaneous or alternating treatments with targeted inhibitors might improve response duration.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biomarkers, Tumor; Carbamates; Cetuximab; Cohort Studies; Colorectal Neoplasms; DNA Mutational Analysis; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Retrospective Studies; Sulfonamides; Thiazoles

Phosphatidylinositide 3' (PI3')-lipid signaling cooperates with oncogenic BRAF(V600E) to promote melanomagenesis. Sustained PI3'-lipid production commonly occurs via silencing of the PI3'-lipid phosphatase PTEN or, less commonly, through mutational activation of PIK3CA, encoding the 110-kDa catalytic subunit of PI3'-kinase-α (PI3Kα). To define the PI3K catalytic isoform dependency of BRAF-mutated melanoma, we used pharmacologic, isoform-selective PI3K inhibitors in conjunction with melanoma-derived cell lines and genetically engineered mouse (GEM) models. Although BRAF(V600E)/PIK3CA(H1047R) melanomas were sensitive to the antiproliferative effects of selective PI3Kα blockade, inhibition of BRAF(V600E)/PTEN(Null) melanoma proliferation required combined blockade of PI3Kα, PI3Kδ, and PI3Kγ, and was insensitive to PI3Kβ blockade. In GEM models, isoform-selective PI3K inhibition elicited cytostatic effects, but significantly potentiated melanoma regression in response to BRAF(V600E) pathway-targeted inhibition. Interestingly, PI3K inhibition forestalled the onset of MEK inhibitor resistance in two independent GEM models of BRAF(V600E)-driven melanoma. These results suggest that combination therapy with PI3K inhibitors may be a useful strategy to extend the duration of clinical response of patients with BRAF-mutated melanoma to BRAF(V600E) pathway-targeted therapies.. Although BRAF(V600E) pathway-targeted therapies elicit melanoma regression, the onset of drug resistance limits the durability of response. Here, we show that combined treatment with PI3K inhibitors significantly forestalled the onset of MEK1/2 inhibitor-resistant disease in BRAF-mutated GEM melanoma models. These results provide a conceptual framework for the combined deployment of BRAF(V600E) plus PI3K pathway-targeted inhibitors in the treatment of a subset of patients with BRAF-mutated melanoma.

Topics: Animals; Carbamates; Cell Line, Tumor; Cell Proliferation; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Melanoma; Melanoma, Experimental; Mice; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; PTEN Phosphohydrolase; Random Allocation; Sulfonamides; Thiazoles

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cetuximab; Colorectal Neoplasms; Humans; Sulfonamides; Thiazoles