Patients with lung cancer who have both ROS1 fusion and concurrent MAPK alterations had worse survival, according to the results of a recent study.

“Activation of the MAPK pathway by multiple genetic alterations can provide the extremely high proliferative ability that persists in the presence of a ROS1-[tyrosine kinase inhibitor], and therefore, leads to drug resistance,” researchers wrote. “Combined inhibition of ROS1 and MEK can be a promising therapeutic strategy that should be explored clinically in patients that have a ROS1 fusion and a MAPK pathway alteration.”

To come to these conclusions, the researchers used MSK-IMPACT to review target large-panel sequencing data in 75 patients treated with ROS1 tyrosine kinase inhibitors (TKIs) and genetic alterations thought to confer resistance.

Eight of the 75 patients (11%) were found to have both ROS1 fusions and MAPK pathway alterations. These patients also had worse overall survival despite having similar initial clinical characteristics.

Of the 8 patients with MAPK pathway alterations, two harbored novel in-frame deletions in MEK1 and MEKK1 that were acquired after ROS1-TKI treatments. Additionally, 2 patients harbored NF1 loss-of-function mutations.

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The researchers found that expression of MEK1del or MEKK1del and knockdown of NF1 in ROS1 fusion-positive cell lines activated MEK/ERK signaling and led to resistance to ROS1 TKIs.

“To overcome MAPK pathway-mediated resistance, we tested the efficacy of combined inhibition of ROS1 and MEK with several inhibitors and found that the combination therapy successfully suppressed the growth of ROS1 fusion positive cells in vitro and in vivo,” the researchers wrote. “As for the optimal types of MEK inhibitors for combination therapy, our results suggest the possibility that selumetinib may be a better partner to be used with ROS1-TKIs because the more commonly used MEK1 inhibitor trametinib activates ERK signaling, likely helping to counteract inhibition of ROS1.”

Disclosure: Some of the authors disclosed financial relationships with health-related companies. For a full list of disclosures, please refer to the original study.

Reference

Sato H, Schoenfeld AJ, Siau E, et al. MAPK pathway alterations correlate with poor survival and drive resistance to therapy in patients with lung cancers driven by ROS1 fusions [published online March 2, 2020]. Clin Can Res. doi: 10.1158/1078-0432.CCR-19-3321