Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC.

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.

Combined Kdm6a and Trp53 Deficiency Drives the Development of Squamous Cell Skin Cancer in Mice.

Cutaneous squamous cell carcinoma (cSCC) has among the highest mutation burdens of all cancers, reflecting its pathogenic association with the mutagenic effects of UV light exposure. Although mutations in cancer-relevant genes such as TP53 and NOTCH1 are common in cSCC, they are also tolerated in normal skin and suggest that other events are required for transformation; it is not yet clear whether epigenetic regulators cooperate in the pathogenesis of cSCC. KDM6A encodes a histone H3K27me2/me3 demethylase that is frequently mutated in cSCC and other cancers. Previous sequencing studies indicate that roughly 7% of cSCC samples harbor KDM6A mutations, including frequent truncating mutations, suggesting a role for this gene as a tumor suppressor in cSCC. Mice with epidermal deficiency of both Kdm6a and Trp53 exhibited 100% penetrant, spontaneous cSCC development within a year, and exome sequencing of resulting tumors reveals recurrent mutations in Ncstn and Vcan. Four of 16 tumors exhibited deletions in large portions of chromosome 1 involving Ncstn, whereas another 25% of tumors harbored deletions in chromosome 19 involving Pten, implicating the loss of other tumor suppressors as cooperating events for combined KDM6A- and TRP53-dependent tumorigenesis. This study suggests that KDM6A acts as an important tumor suppressor for cSCC pathogenesis.

The Next Generation of KRAS Targeting: Reasons for Excitement and Concern.

The development of selective KRASG12C inhibitors that directly inhibit KRAS, an oncogene historically thought to be "undruggable," represents a watershed moment in oncology and developmental therapeutics. Now, as KRAS-targeted therapy moves into its second phase, there is significant excitement and anticipation for durable disease control in tumor types where options remain limited, with clinical trials testing combination therapies, indirect pan-RAS/MAP kinase pathway inhibitors, and active-state RAS(on) inhibitors. However, there is also reason for caution regarding the safety and tolerability of expanded RAS inhibition. This is evidenced by the intolerability of some combination therapies with selective KRASG12C inhibitors and foreshadowed by prior failures of combination therapies in other oncogene-driven tumors. Herein, we review the landscape of and outlook for KRAS-targeted therapies. We specifically focus upon strategies to combat resistance to KRAS-targeted therapies, and discuss the possibility of off-target or unanticipated on-target effects that may limit clinical use.

Mechanisms of Resistance to KRASG12C-Targeted Therapy.

KRAS mutations are among the most common drivers of human carcinogenesis, and are associated with poor prognosis and an aggressive disease course. With the advent of KRASG12C inhibitors, the RAS protein is now targetable, with such inhibitors showing marked clinical responses across multiple tumor types. However, these responses are short-lived due to the development of resistance. Preclinical studies now suggest MAPK reactivation, stimulation of CDK4/6-dependent cell-cycle transition, and immune defects as possible mechanisms of resistance. Devising strategies to overcome such resistance mechanisms, which are a barrier to long-term clinical response, remain an active area of research. SIGNIFICANCE: Although KRAS-targeted cancer therapy is revolutionary, tumors rapidly develop resistance. Understanding the mechanisms driving this resistance and designing combination strategies to overcome it are integral to achieving long-term disease control.