Mutations, drugs drive cancer by blurring growth signals


Genetic mutations in a form of non-small cell lung cancer (NSCLC) may drive tumor formation by blurring cells' perception of key growth signals, according to a new laboratory study. The research could have important implications for understanding and ultimately targeting the defective mechanisms underlying many human cancers.

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Therapeutic genome editing: prospects and challenges


Recent advances in the development of genome editing technologies based on programmable nucleases have substantially improved our ability to make precise changes in the genomes of eukaryotic cells. Genome editing is already broadening our ability to elucidate the contribution of genetics to disease by facilitating the creation of more accurate cellular and animal models of pathological processes. A particularly tantalizing application of programmable nucleases is the potential to directly correct genetic mutations in affected tissues and cells to treat diseases that are refractory to traditional therapies. Here we discuss current progress toward developing programmable nuclease–based therapies as well as future prospects and challenges.

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AXL and acquired resistance to EGFR inhibitors

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A combination of in vitro and in vivo models with validation in human tumors has identified AXL activation as a new mechanism of acquired resistance to EGFR inhibitors in non–small cell lung cancer. The identification of this mechanism, alongside the current development of specific AXL inhibitors, provides the rationale for further studies that may improve treatment for EGFR inhibitor–resistant patients.

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Dual Therapy’s One-Two Punch Knocks Out Drug-Resistant Lung Cancer

UCSF News reports on the latest research of the Bivona Lab into the mechanism of acquired resistance of patients' tumors to targeted drug therapy in non-small cell lung cancer (NSCLC). 

Capitalizing on a rare opportunity to thoroughly analyze a tumor from a lung cancer patient who had developed resistance to targeted drug treatment, UC San Francisco scientists identified a biological escape hatch that explains the resistance, and developed a strategy in mice for shutting it down.

In experiments that combined the drug the patient had taken with a second compound that blocks off this newly discovered resistance pathway, the researchers were able to durably wipe out cancer cells in mice implanted with cells from the drug-resistant tumor.

“Even in cancers that are responding to targeted therapy by conventional criteria, resistance is already developing,” said the senior author of the new study,Trever Bivona, MD, PhD, assistant professor of medicine and member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). “In this work we have begun to crack open the question of why residual disease persists after targeted therapy.”.............

Understanding the biological basis of acquired resistance has proved difficult, partly because patients with late-stage lung cancer rarely undergo surgery, leaving scientists with few drug-resistant tumors to use in research. But as described in the online edition of Cell Reports on Thursday, April 2, 2015, a team of UCSF researchers recently had unusual access to a surgically resected tumor from an EGFR-mutant lung cancer patient who had experienced a substantial, but incomplete, response to erlotinib.

Led by first authors Collin Blakely, MD, PhD, a clinical instructor at UCSF, and Evangelos Pazarentzos, PhD, a postdoctoral fellow, the research group analyzed cells from this tumor using next-generation genome sequencing in an effort to understand how the cells sidestepped erlotinib treatment. They found that the tumor cells retained the EGFR mutation targeted by erlotinib and had not acquired additional cancer-driving mutations, or any other mutations known to confer drug resistance. These results suggested that the cells were still potentially susceptible to erlotinib, but had enlisted some additional mechanism to survive treatment......

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NF-κB-Activating Complex Engaged in Response to EGFR Oncogene Inhibition Drives Tumor Cell Survival and Residual Disease in Lung Cancer 

Published online: April 2, 2015 in Cell Reports

Study Shows Why Some Targeted Cancer Drugs Lose Effectiveness

UCSF News reports on the research of the the Bivona Lab into why certain targeted cancer drugs lose effectiveness over time and how combination therapies could overcome drug resistance.

A protein called YAP, which drives the growth of organs during development and regulates their size in adulthood, plays a key role in the emergence of resistance to targeted cancer therapies, according to a new study led by UC San Francisco researchers.

By precisely identifying the mechanism by which elevated levels of YAP promote the survival of cancer cells, the new work points the way to combination therapies that may overcome resistance to individual targeted drugs, the scientists said.

Though cancer drugs aimed at specific genetic mutations have had some success in recent years, most patients who have a good initial response eventually develop resistance to these therapies, most likely because cancer cells engage alternative survival mechanisms that lie outside the biological pathways targeted by the drugs.

Though oncologists have the option of switching to a different targeted drug after resistance takes hold, many cancer researchers believe that a better strategy would be to forestall cancer cells’ eventual escape routes by using customized combinations of targeted drugs at the outset of therapy.

“Instead of trying to figure out why patients have developed resistance after it has emerged, we need to decipher what survival tactic tumor cells will be most dependent on when they are challenged with targeted therapy,” said the senior author of the study, Trever Bivona, MD, PhD, UCSF assistant professor of medicine and a member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC).

“We want to learn how to wipe out that alternative survival pathway at the beginning of therapy – to pull the rug out from under those cells right away.”


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