The CDK4/6 inhibitors biomarker landscape: The most relevant biomarkers of response or resistance for further research and potential clinical utility

Antonarelli, Gabriele; Taurelli Salimbeni, Beatrice; Marra, Antonio; Esposito, Angela; Locatelli, Marzia Adelia; Trapani, Dario; Pescia, Carlo; Fusco, Nicola; Curigliano, Giuseppe; Criscitiello, Carmen

doi:10.1016/j.critrevonc.2023.104148

Cited by 4 publications

(2 citation statements)

References 139 publications

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“…In flow cytometry assays, MCF7 G55V cells are ~4-fold enriched for viability over MCF7 WT We, and others, have shown that loss of MLH1 mutes Chk2 activation, an event critical for mounting cell cycle arrest in response to endocrine treatment 7,41,55,56 . However, the MLH1 G55V This mutation decreases in VAF after 3 cycles of CDK4/6 inhibition from 2.5% to undetectable (Fig 7D ) unlike the VAF of RB1 deletion, a known driver of resistance to palbociclib [59][60][61][62][63] , which increases after exposure to treatment from 1% to 14% (Fig 7D). In this clinical trial, patient tumors were also independently categorized as either proficient or deficient in MMR based on high blood tumor mutation burden and microsatellite instability 58 .…”

Section: Mlh1 Mutations Drive Varying Degrees Of Endocrine Treatment ...mentioning

confidence: 98%

Aberrant cytoplasmic localization of MLH1 characterizes a sub-clonal breast cancer cell population that seeds recurrence

Mazumder,

DeWitt,

Oropeza

et al. 2024

Preprint

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Mismatch repair loss is a commonly used prognostic and predictive clinical diagnostic across several cancer types. Currently, mismatch repair loss is assessed using bulk tumor approaches to assess genome instability (e.g. tumor mutation burden, microsatellite instability) or by immunohistochemistry for total protein level of individual mismatch repair proteins. Here, we identify a novel mechanism by which mismatch repair proteins are dysregulated that cannot be detected by either of these clinical diagnostic approaches. Sub-clonal mutations in MLH1, a principal mismatch repair gene, detected in tumors from estrogen receptor positive breast cancer patients do not impact abundance of MLH1 protein, nor do they contribute sufficiently to genomic instability to enable detection at the bulk tumor level. However, as we demonstrate here, some of these sub-clonal mutations aberrantly localize MLH1 protein to the cytoplasm, preventing MLH1-mediated activation of the G1 cell cycle checkpoint in response to standard targeted endocrine therapies. The lack of G1 checkpoint activity results in treatment resistance of a sub-clonal persister-like population that remains viable even after long-term exposure to treatment. The dependence on G1 progression, however, renders these sub-clonal populations acutely sensitive to CDK4/6 inhibitors such as palbociclib. Overall, data presented here strongly suggests that aberrant cytoplasmic localization of MLH1 can serve as a predictive biomarker to more accurately predict resistance to endocrine therapy, and sensitivity to combinatorial treatment with CDK4/6 inhibitors. This is particularly important in the adjuvant setting where the risk-benefit ratio for untargeted CDK4/6 inhibitor intervention is narrow. It is possible that these findings have important implications for treatment guidance in other non-breast cancer types as well, where MLH1 mutation is even more frequent.

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Section: Mlh1 Mutations Drive Varying Degrees Of Endocrine Treatment ...mentioning

confidence: 98%

Aberrant cytoplasmic localization of MLH1 characterizes a sub-clonal breast cancer cell population that seeds recurrence

Mazumder,

DeWitt,

Oropeza

et al. 2024

Preprint

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show abstract

“…In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. However, recurrent and metastatic breast cancer often eventually develop resistance to these drugs, and cure is still rare [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Further development of new therapies for refractory breast cancer that do not have conventional mechanisms of action is necessary.…”

Section: Introductionmentioning

confidence: 99%

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

Nagahashi,

Miyoshi

2024

IJMS

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In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.

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EGFR and HER2 hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer

Belli,

Esposito,

Ascione

et al. 2024

Cancer Letters

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The CDK4/6 inhibitors biomarker landscape: The most relevant biomarkers of response or resistance for further research and potential clinical utility

Cited by 4 publications

References 139 publications

Aberrant cytoplasmic localization of MLH1 characterizes a sub-clonal breast cancer cell population that seeds recurrence

Aberrant cytoplasmic localization of MLH1 characterizes a sub-clonal breast cancer cell population that seeds recurrence

Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer

EGFR and HER2 hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer

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