ERK mediates interferon gamma-induced melanoma cell death

Ameya Champhekar; Rachel Heymans; Justin Saco; Guillem Turon Font; Cynthia Gonzalez; Anne Gao; John Pham; June Lee; Ryan Maryoung; Egmidio Medina; Katie M Campbell; Daniel Karin; David Austin; Robert Damioseaux; Antoni Ribas

doi:10.1186/s12943-023-01868-x

ERK mediates interferon gamma-induced melanoma cell death

Mol Cancer. 2023 Oct 6;22(1):165. doi: 10.1186/s12943-023-01868-x.

Authors

Ameya Champhekar¹, Rachel Heymans², Justin Saco^{2

3}, Guillem Turon Font², Cynthia Gonzalez², Anne Gao², John Pham², June Lee², Ryan Maryoung², Egmidio Medina², Katie M Campbell², Daniel Karin^{2

3}, David Austin⁴, Robert Damioseaux^{3

4

5

6}, Antoni Ribas^{7

8

9

10}

Affiliations

¹ Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA. achamphekar@mednet.ucla.edu.
² Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
³ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, 90095, USA.
⁴ California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA.
⁵ Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA.
⁶ Department of Bioengineering, Samueli School of Engineering, University of California, Los Angeles, CA, 90095, USA.
⁷ Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA. aribas@mednet.ucla.edu.
⁸ Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA. aribas@mednet.ucla.edu.
⁹ Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, Los Angeles, CA, 90095, USA. aribas@mednet.ucla.edu.
¹⁰ Parker Institute for Cancer Immunotherapy, San Francisco, CA, 94129, USA. aribas@mednet.ucla.edu.

Abstract

Background: Interferon-gamma (IFNγ) exerts potent growth inhibitory effects on a wide range of cancer cells through unknown signaling pathways. We pursued complementary screening approaches to characterize the growth inhibition pathway.

Methods: We performed chemical genomics and whole genome targeting CRISPR/Cas9 screens using patient-derived melanoma lines to uncover essential nodes in the IFNγ-mediated growth inhibition pathway. We used transcriptomic profiling to identify cell death pathways activated upon IFNγ exposure. Live imaging experiments coupled with apoptosis assays confirmed the involvement of these pathways in IFNγ-mediated cell death.

Results: We show that IFNγ signaling activated ERK. Blocking ERK activation rescued IFNγ-mediated apoptosis in 17 of 23 (~ 74%) cell lines representing BRAF, NRAS, NF1 mutant, and triple wild type subtypes of cutaneous melanoma. ERK signaling induced a stress response, ultimately leading to apoptosis through the activity of DR5 and NOXA proteins.

Conclusions: Our results provide a new understanding of the IFNγ growth inhibition pathway, which will be crucial in defining mechanisms of immunotherapy response and resistance.

Keywords: ERK signaling; IFNγ; Melanoma; Stress response; Tumor growth inhibition.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Apoptosis
Cell Line, Tumor
Humans
Interferon-gamma / metabolism
Interferon-gamma / pharmacology
Melanoma* / genetics
Melanoma* / metabolism
Proto-Oncogene Proteins B-raf / genetics
Skin Neoplasms*

Substances

Interferon-gamma
Proto-Oncogene Proteins B-raf

Abstract

Publication types

MeSH terms

Substances

Grants and funding