Targeting G1/S phase cell-cycle genomic alterations and accompanying co-alterations with individualized CDK4/6 inhibitor–based regimens

Kato, Shumei; Okamura, Ryosuke; Adashek, Jacob J.; Khalid, Noor; Lee, Suzanna; Nguyen, Van; Sicklick, Jason K.; Kurzrock, Razelle

doi:10.1172/jci.insight.142547

Cited by 22 publications

(32 citation statements)

References 43 publications

(24 reference statements)

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“…The presence of significantly co-altered genes within RET fusionpositive NSCLC samples may also provide insight into future directions in overcoming treatment resistance and a combination approach to improve outcomes in this patient population (58,59,61). It will also be important to follow the significance of RET amplifications regarding response to RET inhibition for various cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in these patients the addition of crizotinib, a MET inhibitor, was sufficient to overcome this resistance and provide for response (47). The combination of RET inhibitors with a MET inhibitor or employing a TKI that targets both alterations may be beneficial in these patients (58)(59)(60).…”

Section: Ret and Resistance Mechanisms And Ret As Resistance Mechanismmentioning

confidence: 99%

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Hallmarks of RET and Co-occuring Genomic Alterations in RET-aberrant Cancers

Adashek

Desai

Andreev-Drakhlin³

et al. 2021

Molecular Cancer Therapeutics

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Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers.Herein, we review the registrational data from the selective RETinhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRAS G12C inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Ret and Resistance Mechanisms And Ret As Resistance Mechanismmentioning

confidence: 99%

Hallmarks of RET and Co-occuring Genomic Alterations in RET-aberrant Cancers

Adashek

Desai

Andreev-Drakhlin³

et al. 2021

Molecular Cancer Therapeutics

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“…Melanoma patients with KIT amplification have been reported to derive clinical benefit from imatinib [13] and frequent copy number gains of KIT have been described in squamous cell carcinoma of the lung [14]. Furthermore, CDK4/6 amplifications have been associated with longer PFS in hormone receptor-positive, HER2-negative metastatic breast cancer patients treated with CDK4/6 inhibitors [15]. Finally, RICTOR amplification has been proposed as a mechanism of resistance to TKIs and potential therapeutic target in this setting [16].…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned, CDK4/6 amplifications have been associated with better outcome in breast cancer patients treated with CDK4/6 inhibitors. In lung cancer, recent in vitro research has suggested that the CDK4/6 inhibitor palbociclib in combination with taxanes might be useful in SqCLC [15,26].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Copy Number Variations in Solid Tumors Using a Next Generation Sequencing Custom Panel

Vives-Usano

Peláez

Lladó

et al. 2021

JMP

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Somatic copy number variations (CNV; i.e., amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies. Although FISH is still considered the gold standard for CNV detection, the increasing number of potentially druggable amplifications to be assessed makes a gene-by-gene approach time- and tissue-consuming. Here we investigated the potential of next generation sequencing (NGS) custom panels to simultaneously determine CNVs across FFPE solid tumor samples. DNA was purified from cell lines and FFPE samples and analyzed by NGS sequencing using a 20-gene custom panel in the GeneReader Platform®. CNVs were identified using an in-house algorithm based on the UMI read coverage. Retrospective validation of in-house algorithm to identify CNVs showed 97.1% concordance rate with the NGS custom panel. The prospective analysis was performed in a cohort of 243 FFPE samples from patients arriving at our hospital, which included 74 NSCLC tumors, 148 CRC tumors, and 21 other tumors. Of them, 33% presented CNVs by NGS and in 14 cases (5.9%) the CNV was the only alteration detected. We have identified CNV alterations in about one-third of our cohort, including FGFR1, CDK6, CDK4, EGFR, MET, ERBB2, BRAF, or KRAS. Our work highlights the need to include CNV testing as a part of routine NGS analysis in order to uncover clinically relevant gene amplifications that can guide the selection of therapies.

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“…Among them are gene mutations that represent potential actionable targets (Figure 3). In detail, the loss of PTEN's exons 2-5 may predict sensitivity to mTOR inhibito [13], and CCND1 amplification may predict sensitivity to CDK4/6 inhibitors [14]. The an ysis also revealed an MDM2 amplification, a microsatellite status-stable profile and a lo mutational burden (3 muts/Mb); these results have been described to be associated with low rate of clinical benefit from immunotherapy with immune-checkpoint inhibitors [1 Amplification FGF3 (fibroblast growth factor 3) Amplification FGF4 (fibroblast growth factor 4) Amplification In detail, the loss of PTEN's exons 2-5 may predict sensitivity to mTOR inhibitors [13], and CCND1 amplification may predict sensitivity to CDK4/6 inhibitors [14].…”

Section: Case Reportmentioning

confidence: 99%

Next-Generation Sequencing Whole-Genome Analysis for Targeted Treatment Approach of Metastatic Bartholin Gland Adenocarcinoma: An Emblematic Case Report and Review of the Literature

et al. 2021

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Bartholin gland adenocarcinoma (BGA) is extremely rare and is characterized by high rates of lymph-node recurrence and distant metastases. No effective palliative treatments are available for metastatic BGA; therefore, advanced BGA remains a challenge for gynecologic oncologists. Considering the rarity of this disease and the lack of a standardized approach, the present study aims to discuss the available literature on current therapies for BGA and to describe an emblematic case treated with a novel tailored approach. A postmenopausal woman with advanced BGA was referred to our department for an adequate evaluation, staging and treatment. Notably, we used PET/CT as a fundamental imaging technique for staging and follow-up. The patient underwent primary surgery followed by standard chemotherapy and pelvic radiotherapy. Three months later, she relapsed, with the appearance of multiple metastatic sites. Considering the evident chemoresistance to standard chemotherapy and the absence of valid therapeutic alternatives for this rare cancer, she was treated with a combination of repeated minimally invasive surgical procedures for all the resectable metastatic lesions and innovative approaches comprising, firstly, chemoimmunotherapy with Nivolumab combined with metronomic vinorelbine, which resulted in a clinical response for approximately 7 months. Upon disease progression, we used a targeted systemic approach based on the whole genomic profile of the primary tumor, which showed PTEN loss, which is predictive of a benefit from an mTOR inhibitor, and a CCND1 amplification, which predicts sensitivity to CDK4/6 inhibitors. Therefore, she received Everolimus, resulting in a significant metabolic response that lasted 12 months. Thereafter, upon further progression of the disease, the patient started Palbociclib treatment, which is currently ongoing, with evidence of a metabolic response. The patient has survived for 54 months from diagnosis, with a good performance status. In conclusion, the present paper confirms the lack of efficacy of conventional therapeutic regimens in the context of advanced, recurrent or metastatic adenocarcinomas of the Bartholin gland. The case report shows how a personalized multidisciplinary approach based on repeated minimally invasive surgery and tailored anticancer treatment based on whole-genome sequencing analysis could be effective and associated with prolonged survival in this rare gynecological cancer.

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Targeting G1/S phase cell-cycle genomic alterations and accompanying co-alterations with individualized CDK4/6 inhibitor–based regimens

Cited by 22 publications

References 43 publications

Hallmarks of RET and Co-occuring Genomic Alterations in RET-aberrant Cancers

Hallmarks of RET and Co-occuring Genomic Alterations in RET-aberrant Cancers

Analysis of Copy Number Variations in Solid Tumors Using a Next Generation Sequencing Custom Panel

Next-Generation Sequencing Whole-Genome Analysis for Targeted Treatment Approach of Metastatic Bartholin Gland Adenocarcinoma: An Emblematic Case Report and Review of the Literature

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