Diverse alterations associated with resistance to KRAS(G12C) inhibition

Zhao, Yulei; Murciano‐Goroff, Yonina R.; Xue, Jenny Y.; Ang, Agnes; Lucas, Jessica; Trang, Tran Thi My; Paula, Arnaud Da Cruz; Saiki, Anne Y.; Mohn, Deanna; Achanta, Pragathi; Sisk, Ann Elizabeth; Arora, Kanika; Roy, Rohan S.; Kim, Dongsung; Li, Chuanchuan; Lim, Lee P.; Li, Mark; Bahr, Amber; Houck-Loomis, Brian; Stanchina, Elisa de; Reis‐Filho, Jorge S.; Weigelt, Britta; Berger, Michael F.; Riely, Gregory J.; Arbour, Kathryn C.; Lipford, J. Russell; Li, Bob T.; Lito, Piro

doi:10.1038/s41586-021-04065-2

Cited by 235 publications

(222 citation statements)

References 30 publications

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“…Emergent alterations identi ed at resistance (Figure 1e) included KRAS G12C ampli cation, KRAS mutations (G12A/D/F/LR/S/V, H95L/Q/R, and Y96D/H/N), NRAS mutation (Q61K/R), downstream ERK pathway alterations (BRAF mutations/fusions, MEK1 mutations), RTK activation (MET ampli cation/fusion, RET fusion, EGFR mutations), and MYC ampli cation. Similar to what was previously reported for resistance to KRAS G12C inhibitor monotherapy and in accordance with our preclinical models treated with sotorasib-cetuximab combination, multiple resistance-associated alterations were identi ed in individual patients, with the majority predicted to prevent inhibition of ERK signalling by drug 12 .…”

Section: Full Textsupporting

confidence: 90%

“…Nonetheless, patients treated with these agents eventually acquire resistance and the response to single agent or combination treatment is brief. Several studies have characterized resistance to KRAS G12C monotherapy [10][11][12] . Remarkably, these alterations are highly heterogeneous, including KRAS, BRAF, or MEK mutations, as well as gene ampli cations and fusions, and circulating tumour DNA (ctDNA) analysis typically identi es multiple resistance alterations in the same patient.…”

Section: Full Textmentioning

confidence: 99%

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Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers

Misale

Yaeger

Mezzadra

et al. 2022

Preprint

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KRAS G12C inhibitors, such as sotorasib, have rapidly moved through clinical development and are poised to transform care of patients with KRAS G12C mutant cancers, in particular non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Clinical efficacy is achieved in NSCLC as a single agent and in CRC in combination with anti-EGFR monoclonal antibodies, however, secondary resistance impairs the effects of KRAS G12C blockade. In this work, we sought to determine the mechanisms of acquired resistance to concomitant KRAS-EGFR inhibition. In cell lines, patient-derived xenograft, and patient samples, a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signalling by drug can be detected at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency that does not increase substantially and sometimes disappears over time, with the exception of KRAS G12C amplification which rises in step with tumour marker levels and clinical progression. Here we show that a CRC cell line that acquired resistance to sotorasib-cetuximab combination through KRAS G12C amplification became addicted to these agents and undergoes oncogene-induced senescence upon drug withdrawal. Accordingly, the KRAS G12C signal in circulating DNA from relapsed patients harbouring G12C amplification rapidly recedes upon treatment holiday. These data indicate that KRAS G12C amplification is a recurrent resistance mechanism to KRAS-EGFR co-inhibition and suggest a potential therapeutic vulnerability, whereby therapies that target this senescence response at drug withdrawal may overcome resistance to KRAS G12C-EGFR inhibition.

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confidence: 90%

Section: Full Textmentioning

confidence: 99%

Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers

Misale

Yaeger

Mezzadra

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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“…MET and EGFR amplifications were also detected at progressive disease on sotorasib and co-occurred in one patient. Likewise, FGFR2 amplification was detected in one patient (90).…”

Section: By-pass Mechanisms: Activation Of Rtks and Ras Downstream Si...mentioning

confidence: 86%

“…Exploratory analysis of the CODEBREAK 100 trial showed that KRAS G12C patients who harbor a KEAP1 mutation are likely early-progressors (i.e., patients with an event of progressive disease and PFS<3 months) whereas patients with alterations in effectors of cell cycle, WNT pathway and MAPK pathway are more prevalent in the late-progressor group (i.e., patients with an event of progressive disease and PFS≥3 months) ( 87 ). Zhao et al reported among 43 patients treated with sotorasib - including 36 NSCLC patients - that exceptional responders (i.e., defined as a complete response or a partial response lasting more than 12 months) tend to have a lower plasma KRAS G12C allele frequency and a lower tumor burden at baseline compared to other patients ( 90 ). Based on the clinical efficacy and safety profile, sotorasib was recently approved by FDA for the treatment of advanced KRAS G12C NSCLC patients following at least one prior systemic therapy.…”

Section: Sotorasib and Adagrasib: New Promising Therapeutic Strategie...mentioning

confidence: 99%

“…As for adagrasib, genomic and histologic analysis of pre-treatment samples compared with those obtained at progressive disease on sotorasib were recently reported among 32 NSCLC patients enrolled in CODEBREAK 100 and CODEBREAK 101 clinical trials ( 90 ). Among these, putative mechanisms of acquired resistance were identified in 78% cases.…”

Section: Biological Mechanisms Of Acquired Resistance To Sotorasib An...mentioning

confidence: 99%

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Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies

et al. 2022

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Although KRAS-activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit KRAS failed in the past decade. KRAS mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (i.e., adagrasib, sotorasib) that target specifically KRAS G12C in its GDP-bound state has evidenced an unprecedented success in the treatment of this subgroup of patients. Despite providing pre-clinical and clinical efficacy, several mechanisms of acquired resistance to KRAS G12C inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of KRAS G12C seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRAS G12C inhibitors.

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Prognostic value of baseline genetic features and newly identified TP53 mutations in advanced breast cancer

Zhang

Sun

Zhao³

et al. 2022

Molecular Oncology

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Approximately 30% of breast cancer (BC) patients suffer from disease relapse after definitive treatment. Monitoring BC at baseline and disease progression using comprehensive genomic profiling would facilitate the prediction of prognosis. We retrospectively studied 101 BC patients ultimately experiencing relapse and/or metastases. The baseline and circulating tumor DNA-monitoring cohorts included patients with baseline tumor tissue and serial plasma samples, respectively. Samples were analyzed with targeted next-generation sequencing of 425 cancer-relevant genes. Of 35 patients in the baseline cohort, patients with TP53 mutations (P < 0.01), or CTCF/ GNAS mutations (P < 0.01) displayed inferior disease-free survival, and patients harboring TP53 (P = 0.06) or NOTCH1 (P = 0.06) mutations showed relatively poor overall survival (OS), compared to patients with wild-type counterparts. Of the 59 patients with serial plasma samples, 11 patients who were newly detected with TP53 mutations had worse OS than patients whose TP53 mutational status remained negative (P < 0.01). These results indicate that an inferior prognosis of advanced breast cancer was potentially associated with baseline TP53, CTCF, and NOTCH1 alterations. Newly identified TP53 mutations after relapse and/or metastasis was another potential prognostic biomarker of poor prognosis.

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Diverse alterations associated with resistance to KRAS(G12C) inhibition

Cited by 235 publications

References 30 publications

Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers

Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers

Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies

Prognostic value of baseline genetic features and newly identified TP53 mutations in advanced breast cancer

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