Source: Sos ML. Proc Natl Acad Sci USA. 2012;109:17034-17039.
November 15, 2012
2 min read

Aurora kinase inhibitors effective in SCLC patients with MYC amplification

Source: Sos ML. Proc Natl Acad Sci USA. 2012;109:17034-17039.
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A combined genomic and chemical vulnerability analysis showed Aurora kinase inhibitors are effective in small cell lung cancer cell lines that bear MYC amplification, which occurs in 3% to 7% of patients in this demographic.

The genes recurrently affected by genomic alterations in SCLC include TP53 and RB1, as well as the MYC family genes such as MYC, MYCL1 and MYCN, which are often amplified in an incompatible manner.

“Previous studies did not support a role for Aurora dependency in NSCLC cell lines of different genotypes or implied different MYC family genes in a mixed lung cancer panel, thus indicating that the role of amplified MYC and its dependency on [Aurora B] may differ between different cancer subtypes,” Martin L. Sos, MD, of the department of translational genomics at the University of Cologne in Germany, and colleagues wrote.

To identify therapeutically relevant genome alterations in SCLC, Sos and colleagues analyzed a panel of 60 patient-derived SCLC cell lines. This study involved the screening of a library of 267 compounds across 44 SCLC cell lines, as well as genomic characterization.

The researchers also compared the significant alterations present in the cell line collection to the genetic alterations of a collection of 63 primary SCLC specimens.

In MYC-amplified SCLC cells, Aurora kinase inhibition was associated with G2/M-arrest, inactivation of PI3-kinase signaling and induction of apoptosis, according to study results. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity and was independent of depletion of cytoplasmic levels of MYC.

Besides confirming an overall high similarity of SCLC cell lines and primary tumors, analysis results demonstrated a significant (r=0.83) correlation of copy number alterations in both datasets, comparable to results in other tumor types.

“Building on previous studies, the scaling of both the number of cell lines and the number of compounds afforded identification of vulnerabilities associated with infrequent genome alterations, such as amplifications of FGFR1and MYC,” Sos and colleagues wrote. “In the case of FGFR1 amplification, further studies will be required to clarify the frequency of FGFR1 dependency in SCLC, as other genetic lesions may play a role in the responsiveness to FGFR inhibition.”

The cell line collection captured characteristic events of SCLC, including recurrent deletions of RB1 and PTEN, as well amplification of genes such as FGFR1. Additionally, the researchers identified recurrent and focal amplification of MYCL1, MYCN and MYC in both datasets.

High-level MYCN amplification occurred in about 4% to 6% of cases in both datasets, whereas MYCL1 (8% of primary samples vs. 22% of SCLC cell lines) and MYC amplification (3% of primary samples vs. 15% of SCLC cell lines) were detected with a higher occurrence in SCLC cell lines, according to researchers.

Although major events such as MYC amplification are found in both datasets, overall the significant copy number changes of SCLC differ from those found in NSCLC (r=0.57).

“Our data not only point out the differences in the biology of distinct subtypes of lung cancer but also underscore the differences in oncogenic signaling of MYC gene family members,” Sos and colleagues wrote. “Although amplifications of MYCL1 and MYCN amplifications occur in a mutually exclusive fashion with MYC amplification — suggesting genetic epistasis — they do not segregate with vulnerability to Aurora B inhibition in SCLC.”

Disclosure: The researchers report consulting and lecture fees from AstraZeneca, Atlas-Biolabs, Bayer, Blackfield, Boehringer Ingelheim, Daiichi-Sankyo, Johnson & Johnson, Lilly, Merck KGaA, Roche and Sanofi-Aventis. They also report research support from AstraZeneca, EOS and Merck.