Evidence map›Paper›PMID 38002269›Full record

ArticleBiomolecules2023

A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer.

Prakash Kulkarni, Atish Mohanty, Sravani Ramisetty, Herbert Duvivier, Ajaz Khan, Sagun Shrestha, Tingting Tan, Amartej Merla, Michelle El-Hajjaoui, Jyoti Malhotra and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Biomolecules, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
0.5field-weighted citation impact, top 31% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed, 2 citations in OpenAlex.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 1 institution in 1 country.

Prakash KulkarniDepartment of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA 91010, USA.
Atish MohantyDepartment of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA 91010, USA.ORCID 0000-0003-1464-3165
Sravani RamisettyDepartment of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA 91010, USA.
Herbert DuvivierDepartment of Medical Oncology, City of Hope Atlanta, 600 Celebrate Life Parkway, Newnan, GA 30265, USA.
Ajaz KhanDepartment of Medical Oncology, City of Hope Chicago, 2520 Elisha Avenue, Zion, IL 60099, USA.
Sagun ShresthaDepartment of Medical Oncology, City of Hope Phoenix, 14200 West Celebrate Life Way, Goodyear, AZ 85338, USA.
Tingting TanDepartment of Medical Oncology, City of Hope National Medical Center, Newport Beach Fashion Island, Duarte, CA 92660, USA.
Amartej MerlaDepartment of Medical Oncology, City of Hope, Lancaster, CA 93534, USA.
Michelle El-HajjaouiDepartment of Medical Oncology, City of Hope Medical Center, West Covina, CA 91790, USA.
Jyoti MalhotraDepartment of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA 91010, USA.
Sharad SinghalDepartment of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA 91010, USA.
Ravi SalgiaDepartment of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, 1500 Duarte Rd., Duarte, CA 91010, USA.ORCID 0000-0001-9643-7626
City Of Hope National Medical Center · US

Funding

Modulation of Tumor Microenvironment for Improved Therapy of Pancreatic CancerR01CA247471 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI BATRA, SURINDER K., JAIN, MANEESH · 2020 to 2024
$2.8M
Novel approach to attenuate small cell lung cancer growth and metastasisR01CA218545 · NCI · UNIVERSITY OF NEBRASKA MEDICAL CENTER · PI NASSER, MOHD WASIM · 2018 to 2022
$2.6M
NCI NIH HHS R01 CA218545NCI NIH HHS R01 CA247471
6 · The paper itself

Abstract

Several studies in the last few years have determined that, in contrast to the prevailing dogma that drug resistance is simply due to Darwinian evolution-the selection of mutant clones in response to drug treatment-non-genetic changes can also lead to drug resistance whereby tolerant, reversible phenotypes are eventually relinquished by resistant, irreversible phenotypes. Here, using KRAS as a paradigm, we illustrate how this nexus between genetic and non-genetic mechanisms enables cancer cells to evade the harmful effects of drug treatment. We discuss how the conformational dynamics of the KRAS molecule, that includes intrinsically disordered regions, is influenced by the binding of the targeted therapies contributing to conformational noise and how this noise impacts the interaction of KRAS with partner proteins to rewire the protein interaction network. Thus, in response to drug treatment, reversible drug-tolerant phenotypes emerge via non-genetic mechanisms that eventually enable the emergence of irreversible resistant clones via genetic mutations. Furthermore, we also discuss the recent data demonstrating how combination therapy can help alleviate KRAS drug resistance in lung cancer, and how new treatment strategies based on evolutionary principles may help minimize or even preclude the emergence of drug resistance.

Indexed as

Lung NeoplasmsDrug Resistance, NeoplasmHumansMutationProto-Oncogene Proteins p21(ras)KRAS protein, humanProto-Oncogene Proteins p21(ras)adagrasibdrug resistanceKRAS mutationnon-genetic mechanismssotorasib

Identifiers

PMID38002269
PMCPMC10668935
OpenAlexW4388099161

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.