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Can We Conquer Drug Resistance in Lung Cancer?

At the beginning of the last century lung cancer was a rare disease. However, as early as the end of the 1900s, it had already become the leading cause of preventable death worldwide. In 2016, the disease is expected to cause approximately 158,000 deaths in the United States alone, more than colorectal, breast, and prostate cancers combined. Therefore, finding a better cure for this deadly disease is a pressing need.

Lung cancer has poor prognosis, as it often stays asymptomatic until it is well advanced. Tobacco smoking is responsible for approximately 90% of lung cancer cases, contributing to lung cancer surpassing heart disease as the leading cause of smoking-related mortality. Exposure to other types of carcinogens, such as asbestos, radon, or to a particularly polluted atmosphere, have all been implicated in disease development among non-smokers.

85% of all lung cancer cases are of the non-small cell subtype (NSCLC). Advanced molecular techniques have identified genetic susceptibility in NSCLC linked to amplification of oncogenes and inactivation of tumor suppressor genes. The most important genetic abnormalities detected are mutations involving the ras family of oncogenes.

The Genetic Basis of Drug Resistance

More than a third of NSCLC cases among the Asian population, where tobacco smoking is on the rise, present mutation in the epidermal growth factor receptor (EGFR) gene, which has become a popular target for the development of new anticancer agents. These mutations (deletions in exon 19, and exon 21 L858R mutation) generally arise within the tyrosine kinase domain of the receptor contributing to the expression of a constitutively active form of the protein, which leads to aberrant cell multiplication.

The first generation of inhibitors against the EGFR kinase activity (EGFR-TKIs), such as gefitinib and erlotinib, have been effectively utilized as first-line treatment of advanced NSCLC harboring activating EGFR mutations. However, in these patients drug resistance eventually arise, in most cases as a result of secondary mutations emerging in EGFR (EGFR T790 M, also known as “gatekeeper” mutation). Second and third generation EGFR-TKIs, such as afatinib or osimertinib, were designed to overcome resistance and more potently inhibit EGFR activity. Third generation TKIs are also capable of crossing the blood-brain barrier, and are therefore more likely to have activity in brain metastases, which sometimes develop within a year of treatment.

Given the difficult clinical path of lung cancer treatment which takes patients through disheartening relapse before the more advanced EGFR inhibitors can be prescribed, it has recently been suggested that the third generation EGFR-TKIs should become first-line treatment for EGFR mutated NSCLC.

A New Hope for Treatment Resistant Patients?

It is worth noting that for a subpopulation of NSCLC patients carrying non-canonical mutations in EGFR (exon 20 insertions), there is still no convincing therapy approach since they seem to be refractory to EGFR-TKIs. For these patients combination strategies that hit multiple pathways at the same time have been proposed and novel TKIs are currently being investigated.

To address the need of finding new treatments for this subpopulation of patients, researchers at CrownBio have developed a unique set of patient-derived models (patient-derived xenograft, PDX) that specifically carry non canonical EGFR mutations and that have been trialed with a range of EGFR inhibitors – including first, second, and third generation TKIs as well as Erbitux® (cetuximab), an anti-EGFR antibody that binds to the receptor to inhibits its activity.

Similarly to patients in the clinic these newly developed models showed poor response to standard of care TKIs. More importantly this study was the first one to report a poor outcome following cetuximab treatment in this class of NSCLC, suggesting that CrownBio’s newly developed models represents invaluable assets to predict a patient’s response and for preclinical investigation of drug efficacy before new agents enter the clinic.

CrownBio’s NSCLC models have already been successfully utilized in preclinical research to validate the antitumor efficacy of novel compounds or novel combination strategies.

For more information on CrownBio’s comprehensive collection of NSCLC PDX models visit HuBase, our curated, online, searchable database of phenotypic and genotypic data, patient information, growth curves, and standard of care treatment for our HuPrime® PDX models. Alternatively email us today for a copy of our Models of Resistance Application Note.

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