KRAS in NSCLC: State of the Art and Future Perspectives

Abstract

In NSCLC, KRAS mutations occur in up to 30% of all cases, most frequently at codon 12 and 13. KRAS mutations have been linked to adenocarcinoma histology, positive smoking history, and Caucasian ethnicity, although differences have been described across KRAS mutational variants subtypes. KRAS mutations often concur with other molecular alterations, notably TP53, STK11, and KEAP1, which could play an important role in treatment efficacy and patient outcomes. For many years, KRAS mutations have been considered undruggable mainly due to a high toxicity profile and low specificity of compounds. Sotorasib and adagrasib are novel KRAS inhibitors that recently gained FDA approval for pre-treated KRAS mutant NSCLC patients, and other molecules such as GDC-6036 are currently being investigated with promising results. Despite their approval, the efficacy of these drugs is lower than expected and progression among responders has been reported. Mechanisms of acquired resistance to anti-KRAS molecules typically involves either on target secondary mutations (e.g., G12, G13, Q61H, R68S, H95, Y96C, V8L) or off-target alterations. Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.

Atherosclerosis is a smooth muscle cell-driven tumor-like disease

“…S6A ). The KRAS G12D mutant was chosen because KRAS is one of the most commonly mutated genes associated with progression of multiple types of cancer( 45 ), the oncogenic KRAS G12D was reported to drive tumorigenesis through oxidative DNA damage( 46 ) and genomic instability, and in particular, constitutively activated KRAS (e.g., KRAS G12D ) triggers at least 3 cancer-associated signaling pathways, including NFʺB, PI3K, and MAPK ( 47–49 ), which were hyperactivated in SDCs ( Fig. 3, B-G ).…”

High expression of transcription factor POU2F1 confers improved survival on smokers with lung adenocarcinoma: a retrospective study of two cohorts

“…Analyses were performed using the immunoreactive score (IRS) (37) deriving semiquantitative immunohistochemistry analysis. For the IRS, an ordinal category of the percentage of nuclear positive tumor cells (i.e., 0: no positive cells, 1: <10% positive cells, 2: 10-50% positive cells, 3: 51-80% positive cells, 4: >80% positive cells) is multiplied by the staining intensity (0, 1, 2, 3) and categorized as negative (0-1), mildly positive (2-3), moderately positive (4-8) and strongly positive (9)(10)(11)(12). For statistical analysis, negative and mildly positive specimens (IRS ≤3) were summarized as 'POU2F1 low' and moderate to strongly positive ones (IRS 4-12) were summarized as 'POU2F1 high'.…”

Targeted Therapies for Previously “Undruggable” KRAS-Mutated Non–Small Cell Lung Cancer: A Review of Sotorasib and Adagrasib

“…Despite demonstrating response rates of approximately 40% in pivotal phase II clinical trials, anti-KRAS therapies have proven less efficacious than treatments targeting other actionable mutations in NSCLC. 14 This disparity may be attributable to a myriad of factors present in KRAS-mutated NSCLC, including multiple intrinsic drug resistance mechanisms, concurrent molecular alterations, intratumor RAS-mutant heterogeneity, and suboptimal immunogenic profiles. 14,39,40 To address these challenges, several innovative treatment approaches are being pursued.…”

“…14 This disparity may be attributable to a myriad of factors present in KRAS-mutated NSCLC, including multiple intrinsic drug resistance mechanisms, concurrent molecular alterations, intratumor RAS-mutant heterogeneity, and suboptimal immunogenic profiles. 14,39,40 To address these challenges, several innovative treatment approaches are being pursued. For example, KRAS mutations are linked with a pro-inflammatory microenvironment, and ongoing research is assessing the efficacy of ICIs, either alone or in combination with anti-KRAS therapy.…”