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A CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC

Nicholas Dompe1, Christiaan Klijn2, Sara A Watson1

  • 1Department of Discovery Oncology, Genentech Inc., South San Francisco, CA, United States of America.

Plos One
|June 19, 2018
PubMed

Insights

Targeting MAPK7 can sensitize KRAS-mutant non-small cell lung cancer (NSCLC) to MEK inhibitors. This combination therapy, involving MAPK7 inhibition and MEK inhibitor cobimetinib, showed improved tumor growth inhibition in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Activating mutations in KRAS are common oncogenic drivers in non-small cell lung cancer (NSCLC).
  • Current therapies targeting KRAS-mutant NSCLC are limited, and MEK inhibitors, despite targeting the RAS/MAPK pathway, have shown clinical ineffectiveness.
  • There is a critical need for novel therapeutic strategies to overcome resistance to MEK inhibitors in KRAS-mutant NSCLC.

Purpose of the Study:

  • To identify novel therapeutic targets that can sensitize KRAS-mutant NSCLC cells to MEK inhibitor treatment.
  • To validate the role of identified targets in overcoming MEK inhibitor resistance.
  • To evaluate the efficacy of combination therapy targeting MAPK7 and MEK in preclinical models of KRAS-mutant NSCLC.

Main Methods:

  • Utilized a CRISPR screening approach to identify genes that sensitize KRAS-mutant NSCLC cells to MEK inhibitors.
  • Validated hits through orthogonal methods including genetic knockdown and pharmacological inhibition.
  • Assessed the impact of MAPK7 inhibition on MAPK signaling reactivation.
  • Evaluated the efficacy of combined genetic knockdown of MAPK7 and MEK inhibition (cobimetinib) in KRAS-mutant NSCLC xenograft models.

Main Results:

  • CRISPR screening identified components of the RAS/MAPK pathway and highlighted MAPK7 as a significant novel target.
  • MAPK7 inhibition was shown to attenuate the reactivation of MAPK signaling during long-term MEK inhibition.
  • Combined genetic knockdown of MAPK7 and treatment with cobimetinib significantly inhibited tumor growth in a KRAS-mutant NSCLC xenograft model.

Conclusions:

  • MAPK7 plays a crucial role in mediating pathway reactivation in response to MEK inhibition in KRAS-mutant NSCLC.
  • MAPK7 represents a promising therapeutic target for combination therapy with MEK inhibitors.
  • This combination strategy offers a potential new avenue for treating patients with KRAS-mutant NSCLC.

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