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

Abstract

The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma (LUAC) are poorly characterized. We performed an integrative analysis of genomic, transcriptomic and proteomic data from early-stage and chemo-refractory LUAC and identified three robust subsets of KRAS-mutant LUAC dominated, respectively, by co-occurring genetic events in STK11/LKB1 (the KL subgroup), TP53 (KP) and CDKN2A/B inactivation coupled with low expression of the NKX2-1 (TTF1) transcription factor (KC). We further reveal biologically and therapeutically relevant differences between the subgroups. KC tumors frequently exhibited mucinous histology and suppressed mTORC1 signaling. KL tumors had high rates of KEAP1 mutational inactivation and expressed lower levels of immune markers, including PD-L1. KP tumors demonstrated higher levels of somatic mutations, inflammatory markers, immune checkpoint effector molecules and improved relapse-free survival. Differences in drug sensitivity patterns were also observed; notably, KL cells showed increased vulnerability to HSP90-inhibitor therapy. This work provides evidence that co-occurring genomic alterations identify subgroups of KRAS-mutant LUAC with distinct biology and therapeutic vulnerabilities.

Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer

“…We and others previously demonstrated that molecular alterations commonly found in NSCLC have distinct effects on the therapeutic response to antineoplastic treatment regimens (7)(8)(9)(10). The recent study by Skoulidis and colleagues demonstrated that co-occurring genetic alterations in serine/threonine kinase 11/ liver kinase B1 (STK11/LKB1), TP53, and CDKN2A/B (cyclin-dependent kinase inhibitor 2A/B) characterize 3 major subgroups of KRAS-mutant lung adenocarcinoma (10).…”

“…The recent study by Skoulidis and colleagues demonstrated that co-occurring genetic alterations in serine/threonine kinase 11/ liver kinase B1 (STK11/LKB1), TP53, and CDKN2A/B (cyclin-dependent kinase inhibitor 2A/B) characterize 3 major subgroups of KRAS-mutant lung adenocarcinoma (10). KRAS/TP53 tumors were associated with higher levels of somatic mutations, inflammatory markers, and immune checkpoint effector molecules and improved relapse-free survival.…”

Targeting the KRAS Pathway in Non-Small Cell Lung Cancer

“…Skoulidis et al [37] have defined three subsets of KRASmutant lung cancer with concurrent mutations in STK11/LKB1, TP53, and CDKN2A/B. These mutations are often acquired over time, especially with chemotherapy treatment.…”

“…Additional prospective studies are required to further validate these findings. The CDKN2A/B subtype is associated with distinct pathological characteristics such as invasive mucinous histology, low TTF1 expression, and suppressed mTORC1 signaling [37].…”

Possible application of circulating free tumor DNA in non-small cell lung cancer patients

“…J Thorac Dis 2017;9(Suppl 13):S1364-S1372 jtd.amegroups.com to immune checkpoint blockade are lower in comparison with the double mutant tumors (47). KRAS mutations indicate a poor outcome of the patients and currently there is not any efficient targeted therapy for this disease (48).…”