Preclinical Evaluation of [I]-Sotorasib for the Imaging of Kirsten Rat Sarcoma G12C Mutant Tumors.

Kirsten rat sarcoma (KRAS) is a frequently mutated oncogene responsible for several oncogenic KRAS variants and for driving tumor proliferation. Some nonsmall cell lung cancer (NSCLC) tumors exhibit KRAS G12C mutations, which can be targeted for inhibition using covalent and more recently noncovalent inhibitors. Sotorasib was the first FDA-approved G12C inhibitor that has shown efficacy in lung cancer patients, but with mixed responses.

Pharmacological restoration of GTP hydrolysis by mutant RAS.

Approximately 3.4 million patients worldwide are diagnosed each year with cancers that have pathogenic mutations in one of three RAS proto-oncogenes (KRAS, NRAS and HRAS). These mutations impair the GTPase activity of RAS, leading to activation of downstream signalling and proliferation.

Modeling lung adenocarcinoma metastases using patient-derived organoids.

Approximately 50% of patients with surgically resected early-stage lung cancer develop distant metastasis. At present, there is no in vivo metastasis model to investigate the biology of human lung cancer metastases. Using well-characterized lung adenocarcinoma (LUAD) patient-derived organoids (PDOs), we establish an in vivo metastasis model that preserves the biologic features of human metastases.

In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAF lung adenocarcinoma.

The current targeted therapy for BRAF-mutant lung cancer consists of a dual blockade of RAF/MEK kinases often combining dabrafenib/trametinib (D/T). This regimen extends survival when compared to single-agent treatments, but disease progression is unavoidable. By using whole-genome CRISPR screening and RNA sequencing, we characterize the vulnerabilities of both persister and D/T-resistant cellular models.

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 61. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer. Nevertheless, KRAS mutations account for only around 15% of KRAS-mutated cancers, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations.

Insights into how adeno-squamous transition drives KRAS inhibitor resistance.

The histologic transformation of adenocarcinoma (ADC) to squamous cell carcinoma (SCC), known as adeno-squamous transition or AST, is frequently observed in patients with lung cancer undergoing cancer therapy. In this issue, Tong and colleagues investigate genetic and epigenetic mechanisms that drive AST to confer resistance to KRAS inhibitors in preclinical models and patients.

Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.

The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target.

Outcomes of Combination Platinum-Doublet Chemotherapy and Anti-PD(L)-1 Blockade in KRASG12C-Mutant Non-Small Cell Lung Cancer.

Background: Direct KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described.

Clinical and Genomic Features of Response and Toxicity to Sotorasib in a Real-World Cohort of Patients With Advanced -Mutant Non-Small Cell Lung Cancer.

Purpose: With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced -mutant non-small cell lung cancer (NSCLC), there is a new need to identify factors associated with activity and toxicity among patients treated in routine practice.

Materials And Methods: We conducted a multicenter retrospective study of patients treated with sotorasib outside of clinical trials to identify factors associated with real-world progression free survival (rwPFS), overall survival (OS), and toxicity.

Results: Among 105 patients with advanced -mutant NSCLC treated with sotorasib, treatment led to a 5.

Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.

KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation.

Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100.

JCO In the longest follow-up, to our knowledge, for a KRAS inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with G12C-mutated advanced non-small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical trial (ClinicalTrials.gov identifier: NCT03600883). This multicenter, single-group, open-label phase I/phase II trial enrolled 174 patients with G12C-mutated, locally advanced or metastatic NSCLC after progression on prior therapies.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small-cell lung cancer.

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.

With one eye on the future.

In the past 20 years we have seen the rise of a new era of cancer research that moved its focus away from the cancer cell itself and revealed a complexity of interactions, both within the tumor and with the host, that ultimately dictate the evolution and progression of the disease. We have witnessed the development of immunotherapies that changed the fate of many patients and new diagnostic strategies with the potential of changing clinical practice. In this article, several experts discuss what lies ahead.

Immune biomarkers and response to checkpoint inhibition of BRAF and BRAF non-V600 altered lung cancers.

Background: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours.

Methods: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020.

Diverse alterations associated with resistance to KRAS(G12C) inhibition.

Inactive state-selective KRAS(G12C) inhibitors demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib.

The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS.

Recently reported to be effective in patients with lung cancer, KRAS inhibitors bind to the inactive, or guanosine diphosphate (GDP)–bound, state of the oncoprotein and require guanosine triphosphate (GTP) hydrolysis for inhibition. However, KRAS mutations prevent the catalytic arginine of GTPase-activating proteins (GAPs) from enhancing an otherwise slow hydrolysis rate. If KRAS mutants are indeed insensitive to GAPs, it is unclear how KRAS hydrolyzes sufficient GTP to allow inactive state–selective inhibition.

Suppressing Nucleotide Exchange to Inhibit KRAS-Mutant Tumors.

Guanine nucleotide exchange factors (GEF) control the rate-limiting step of physiologic RAS activation. In this issue of , Hofmann and colleagues describe the discovery of a selective inhibitor targeting the GEF, SOS1, along with its preclinical effects in suppressing KRAS-mutant tumor growth..

Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma.

Purpose: is the most common mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected -mutant lung adenocarcinoma.

Treatment Outcomes and Clinical Characteristics of Patients with KRAS-G12C-Mutant Non-Small Cell Lung Cancer.

Purpose: mutations are identified in approximately 30% of patients with non-small cell lung cancer (NSCLC). Novel direct inhibitors of G12C have shown activity in early-phase clinical trials. We hypothesized that patients with G12C mutations may have distinct clinical characteristics and responses to therapies.

Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients.

KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing pursuit in precision oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in ∼13% of lung adenocarcinomas and, at a lower frequency, in other cancers.