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Celebrating the 10th Anniversary

A decade of discoveries in Cancer Discovery. For the community. By the Community.


Their impactful studies. In their words.


Ferdinandos Skoulidis, MD
MD Anderson Cancer Center
John Heymach, MD, PhD
MD Anderson Cancer Center
Michael Goldberg
University of Washington
Danielle Greenawalt, PhD
Bristol-Meyers Squibb
William Geese, PhD
Bristol-Meyers Squibb
Lee Albacker, PhD
Foundation Medicine
Daniel Shin, MD, PhD
UCLA Jonsson Comprehensive Cancer Center
Antoni Ribas, MD, PhD
UCLA Jonsson Comprehensive Cancer Center

Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities
August 2015

STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma
July 2018

Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations
February 2017


Q: What unanswered questions in the field were these studies addressing?

A: (Ferdinandos Skoulidis and John Heymach) The main motivation behind these studies was a desire to untangle the pervasive molecular diversity of KRAS mutant lung tumors and develop a framework for their molecular stratification that could inform a more personalized approach to therapy.

A: (Lee Albacker) We were assessing if there are genomic alterations that would affect response to checkpoint inhibitors. When we started this work in 2016, the field of checkpoint inhibitor biomarkers was wide open.

A: (Michael Goldberg) We were broadly trying to find biomarkers that would better predict response to immunotherapies in patients with lung adenocarcinomas. We were also motivated to find evidence of alternative mechanisms of immune evasion suggested by patients whose tumors harbored high mutational burden but did not express PD-L1.

A: (Daniel Shin and Antoni Ribas) We reasoned that analyzing potential genetic alterations in biopsies of patients who did not respond to immune checkpoint blockade therapy for melanoma may allow elucidating the mechanistic basis for response and resistance to cancer immunotherapies. We first discovered that occasional cases of patients who initially responded and then relapsed had loss-of-function mutations in JAK1 or JAK2, which are the two kinases required for signaling from the interferon-gamma receptor. We then analyzed if the same kind of mutations were present in patients who did not respond to immune checkpoint blockade upfront, and found a case with melanoma and one with MSI high colon cancer with the same kind of mutations.


Q: What surprised or excited you most about the findings?

This was an exciting discovery because it suggested that mutations in a single gene could potentially account for de novo resistance to immunotherapy.

A: (Ferdinandos Skoulidis and John Heymach) We were struck by the direct and profound impact of KRAS co-mutations – and particularly co-alterations involving the STK11 tumor suppressor gene – on the composition of the tumor immune microenvironment and clinical outcomes with immune checkpoint inhibitors. STK11 inactivation rendered tumors immunologically inert and poorly responsive to PD1/PD-L1 inhibition. This was an exciting discovery because it suggested that mutations in a single gene could potentially account for a large fraction of patients with KRAS-mutant lung tumors that exhibit de novo resistance to immunotherapy.

A: (Lee Albacker) At the time, it was surprising to find that mutational burden and PD-L1 IHC were uncorrelated, though we didn’t end up publishing that result on its own. We also found that STK11 alterations were highly enriched in lung adenocarcinomas with high mutational burden and negative PD-L1 IHC, which suggested STK11 alterations had a role in blocking immune responses to tumors that should harbor multiple neoantigens. Our collaborators at MD Anderson found STK11 alterations were enriched in lung adenocarcinomas that had a cold expression profile. We decided to combine our results to make a more complete study.

A: (Danielle Greenawalt) The importance of not only considering individual molecular biomarkers, but also the interplay between them was exciting. Being able to analyze multiple genomic markers, such as tumor mutation burden, KRAS, STK11 and TP53 mutation status provided us insight into resistance mechanisms of known lung driver mutations.

A: (William Geese) What was particularly exciting about these findings is that in KRAS-mutant lung adenocarcinoma, STK11 represents a common driver of primary resistance to immune checkpoint inhibitor therapy. This provides the framework to investigate the mechanisms underlying primary resistance associated with this genomic abnormality, ultimately helping to inform on novel combinations/treatment modalities in the future to address this difficult-to-treat population of patients.

A: (Daniel Shin and Antoni Ribas) These were the first evidence of genetic alterations that led to primary resistance to checkpoint blockade immunotherapy. They are rare, but their discovery provided an important clue to understand that the interferon-gamma signaling pathway is critically involved in response and resistance to immune checkpoint blockade therapy. Our functional analyses to study the effects of the JAK1 or JAK2 genetic loss provided evidence that they are the consequence of an immuno-editing process to inhibit interferon-gamma signaling in cancer cells.


Q: What have been the papers’ greatest impacts in the years to follow?

A: (Ferdinandos Skoulidis and John Heymach) This work’s most enduring impact has been the elucidation of co-mutations as modifiers of the biology and therapeutic response of KRAS-mutant lung adenocarcinoma and the identification of inactivating STK11 somatic mutations as a major genomic driver of primary resistance to immunotherapy with PD-1/PD-L1 inhibitors. Emerging evidence that STK11 and KEAP1 alterations may also shape clinical outcomes with KRASG12C inhibitors further underscores their significance for the future development of precision therapeutic strategies for KRAS-mutant non-small cell lung cancer.

A: (Danielle Greenawalt) Deeper understanding of the role of concomitant mutations in STK11 and KRAS in response to immune checkpoint inhibitors has allowed the field to pursue combinations, novel therapies and ensure that we are delivering the right treatments for patient benefit.

A: (William Geese) This study established the clinical relevance of STK11 on immune checkpoint inhibitor efficacy and provided further evidence for the importance of genomic profiling above and beyond traditional biomarkers of immune checkpoint inhibitor efficacy (e.g. PD-L1 status, tumor mutation burden) to inform treatment outcomes in KRAS-mutant lung adenocarcinoma.

A: (Daniel Shin and Antoni Ribas) Our study demonstrated the significant role of tumor interferon-gamma signaling to mediate immunotherapy response. The understanding that interferon signaling in the tumor microenvironment is required for response to cancer immunotherapy allowed postulating that combination therapies that increase tumor interferon signaling may overcome immune resistance, and such approaches are being tested in preclinical models and in clinical trials in humans.


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