New RAF-targeted Therapeutic Shows Early Promise Against Tumors With BRAF and RAS Mutations

Excerpt:

“The new investigational anticancer therapeutic BGB-283, which targets the RAF family of proteins, was safe, tolerable, and showed signs of clinical activity in patients who had a range of types of cancer with mutations in BRAF, KRAS, and NRAS, according to results from a phase I clinical trial presented here at the AACR Annual Meeting 2016, April 16-20.

“ ‘BRAF gene mutations fuel cancer cell proliferation and survival in a number of types of cancer, including melanoma, and thyroid and colorectal cancers,’ said Jayesh Desai, FRACP, a medical oncologist at The Royal Melbourne Hospital in Melbourne, Australia. ‘In melanoma, the BRAF V600E mutation predominates, and specific inhibitors of the BRAF V600E mutant protein have been approved for treating patients with melanoma with BRAF V600E gene mutations.’ ”

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Clinical Trial of a New "panRAF" Inhibitor Enrolls First Melanoma Patient

“A patient has become the first to receive a new ‘resistance-busting’ experimental skin cancer drug with the launch of a phase I clinical trial.

“The patient has received a new panRAF inhibitor – a new type of drug under development to address the problem of drug resistance in advanced skin cancer and a number of other cancer types.

“The trial is the culmination of a pioneering research programme to design, synthesise and develop the new drug class, led by scientists at The Institute of Cancer Research, London, and the Cancer Research UK Manchester Institute at The University of Manchester.

“It is starting just three months after a major publication in the journal Cancer Cell described the potential of this new drug class, which is potentially able to treat melanomas – the most serious type of skin cancer – that do not respond or have become resistant to existing therapies.

“The phase I trial of the drug – which is yet to be given a formal name and is currently known as BAL3833/CCT3833 – is sponsored by The Institute of Cancer Research (ICR) and The Royal Marsden NHS Foundation Trust.”


Conference Abstract – MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients With Acquired Resistance to Combined RAF/MEK Inhibition

“Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP–ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. This study represents an initial clinical genomic study of acquired resistance to combined RAF/MEK inhibition in BRAF-mutant melanoma, using WES and RNA-seq. The presence of diverse resistance mechanisms suggests that serial biopsies and genomic/molecular profiling at the time of resistance may ultimately improve the care of patients with resistant BRAF-mutant melanoma by specifying tailored targeted combinations to overcome specific resistance mechanisms.”

Editor’s note: We previously covered the benefits of a dabrafenib/trametinib combo for advanced-stage melanoma. However, some patients’ tumors become resistant to this drug combination and new treatment routes need to be considered. This study is exploring how molecular testing of specific genetic mutations in patients’ tumors might be used to help guide treatment decisions after they become resistant to the dabrafenib/trametinib combo.


Novartis Revolutionizes Clinical Trials for Targeted Cancer Drugs


Someone had to do it; now it looks like Novartis may be the first. The pharma company’s new series of clinical trials, SIGNATURE (also known as, ‘bring the protocol to the patient,’ or  ‘P2P’), is recruiting patients with different cancers to receive investigational targeted drugs selected to match the distinct genetic changes found in each patient’s tumor. Continue reading…


Phosphoproteomic Characterization of DNA Damage Response in Melanoma Cells Following MEK/PI3K Dual Inhibition

“Growing evidence suggests that successful intervention in many human cancers will require combinations of therapeutic agents. Critical to this effort will be a detailed understanding of the crosstalk between signaling networks that modulate proliferation, cell death, drug sensitivity, and acquired resistance. Here we investigated DNA-damage signaling elicited by small-molecule inhibitors against MAP/ERK kinase (MEK) and PI3K in melanoma cells. This work, performed using cutting-edge mass spectrometry proteomics, uncovered a burst of signaling among proteins in the DNA-damage pathway upon initiation of the cell-death program by agents targeting the RAS–RAF–MEK and PI3K–AKT–mTOR pathways. These signals may prove important to the short- and long-term sensitivity of tumor cells to MEK- and PI3K-targeted therapies.”


A Melanocyte Lineage Program Confers Resistance to MAP Kinase Pathway Inhibition

“Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF–MEK–ERK signalling for tumour cell growth1. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma23; however, resistance to these agents remains a formidable challenge24. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF–MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF–MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOSNR4A1NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF–MEK–ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics.”


In Vivo MAPK Reporting Reveals the Heterogeneity in Tumoral Selection of Resistance to RAF Inhibitors

“Activation of the ERK1/2 mitogen-activated protein kinases (MAPKs) confers resistance to the RAF inhibitors vemurafenib and dabrafenib in mutant BRAF-driven melanomas. Methods to understand how resistance develops are important to optimize the clinical utility of RAF inhibitors in patients. Here we report the development of a novel ERK1/2 reporter system that provides a non-invasive, quantitative and temporal analysis of RAF inhibitor efficacy in vivo. Use of this system revealed heterogeneity in the level of ERK1/2 reactivation associated with acquired resistance to RAF inhibition. We identified several distinct novel and known molecular changes in resistant tumors emerging from treatment-naïve cell populations including BRAF V600E variants and HRAS mutation, both of which were required and sufficient for ERK1/2 reactivation and drug resistance. Our work offers an advance in understanding RAF inhibitor resistance and the heterogeneity in resistance mechanisms, which emerge from a malignant cell population.”


mTORC1 Status Dictates Tumor Response to Targeted Therapeutics

“Genomics has revolutionized and personalized our approach to cancer therapy, with clinical trials now frequently involving patient stratification based on tumor genotype. Rational drug design specifically targeting the most common genetic events and aberrantly regulated pathways in human cancers makes this approach possible. However, our understanding of the wiring of oncogenic signaling networks and the key downstream effectors driving human cancers is incomplete, limiting our ability to predict clinical responses or identify mechanisms of resistance to targeted therapeutics. Recent studies in independent cancer lineages driven by distinct oncogenic signaling events point to a common downstream target, the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1), which dictates the cellular and clinical response to pathway-specific inhibitors. mTORC1 is a highly integrated signaling node that promotes anabolic cell growth and proliferation and lies downstream of multiple oncogenes and tumor suppressors, including those influencing the PI3K-Akt and RAS-RAF-MEK-ERK pathways. Studies are now suggesting that to effectively target the major oncogenic signaling pathway in a given tumor, mTORC1 must be inhibited, and that its sustained activation is a major mechanism of resistance to such targeted therapies.”


Mechanisms of Targeted Therapy Resistance Take a De-TOR

“The effectiveness of cancer therapeutics targeting signal transduction pathways is comprised of a diversity of mechanisms that drive de novo or acquired resistance. Two recent studies identify mTOR activation as a point of convergence of mechanisms that cause resistance to inhibitors of the Raf-MEK-ERK and PI3K signaling.”