Title: Paracrine ERBB signalling as a predictive indicator of progression in early stage KRAS-driven lung adenocarcinoma
Funder: Cancer Research UK

Abstract: Background Cancers of the lung kill more people annually than cancers of any other organ. These cancers are typically detected late, are highly heterogeneous and refractory to treatment. Early detection and early intervention offer the best hope for improving patient outcomes but our understanding of early disease is rudimentary. Unlike many other deep-tissue cancers, the at-risk cohort for lung cancer in Europe is largely well-defined – early detection of predictive biomarkers could thus show substantial & immediate clinical benefit. Adenocarcinoma (LuAd) represents the largest subtype of lung cancer and driver mutations in KRAS are present in over 35% of LuAd. There are presently no predictive biomarkers for progression of KRAS mutant LuAd from benign to malignant cancer, nor are there proven therapeutic strategies for treatment of this cohort. My lab has recently identified a surprising requirement for signalling through ERBB RTKs for development of autochthonous KRAS-driven LuAd. We found a pronounced increase in ERBB signalling activity during progression of early stage disease that involves cross-talk between tumour and stromal cells, especially macrophages. We hypothesise that this increased ERBB signalling may be exploited for actionable early detection of KRAS-driven LuAd progression to malignancy. Aims 1) Determine the identity and tumour disposition of individual cells exhibiting elevated ERBB network expression/activity during early stage progression in a mouse model of KRas-driven LuAd. 2) Determine the prevalence & predictive implications of such cells in human LuAd patient samples. 3) Ascertain the functional role of phospho-ERBB2 positive macrophages on maintenance & progression of KRas LuAd. Methods We will employ single cell differential expression analysis to definitively characterise the tumour and stromal populations that show elevated ERBB activity in an autochthonous mouse model of KRAS LuAd. These data will inform analysis of an extensive human LuAd tissue micro-array, comprising early and advanced disease, to establish any predictive relationship between ERBB signalling and progression from early disease. We will use genetic and pharmacological means to suppress tumour-associated macrophages to determine the influence on tumour ERBB-RAS pathway activity and progression from early stage disease. Use Our data will determine the value of ERBB signalling as a predictive indicator of KRAS LuAd progression. Our detection methods could be rapidly applied in the clinic and moreover guide patient-specific cancer therapy with existing approved drugs.

Lay abstract: Background Cancers of the lung kill more people annually than cancers of any other organ. These cancers are typically detected late, are highly heterogeneous and refractory to treatment. Early detection and early intervention offer the best hope for improving patient outcomes but our understanding of early disease is rudimentary. Unlike many other deep-tissue cancers, the at-risk cohort for lung cancer in Europe is largely well-defined – early detection of predictive biomarkers could thus show substantial & immediate clinical benefit. Adenocarcinoma (LuAd) represents the largest subtype of lung cancer and driver mutations in KRAS are present in over 35% of LuAd. There are presently no predictive biomarkers for progression of KRAS mutant LuAd from benign to malignant cancer, nor are there proven therapeutic strategies for treatment of this cohort. My lab has recently identified a surprising requirement for signalling through ERBB RTKs for development of autochthonous KRAS-driven LuAd. We found a pronounced increase in ERBB signalling activity during progression of early stage disease that involves cross-talk between tumour and stromal cells, especially macrophages. We hypothesise that this increased ERBB signalling may be exploited for actionable early detection of KRAS-driven LuAd progression to malignancy. Aims 1) Determine the identity and tumour disposition of individual cells exhibiting elevated ERBB network expression/activity during early stage progression in a mouse model of KRas-driven LuAd. 2) Determine the prevalence & predictive implications of such cells in human LuAd patient samples. 3) Ascertain the functional role of phospho-ERBB2 positive macrophages on maintenance & progression of KRas LuAd. Methods We will employ single cell differential expression analysis to definitively characterise the tumour and stromal populations that show elevated ERBB activity in an autochthonous mouse model of KRAS LuAd. These data will inform analysis of an extensive human LuAd tissue micro-array, comprising early and advanced disease, to establish any predictive relationship between ERBB signalling and progression from early disease. We will use genetic and pharmacological means to suppress tumour-associated macrophages to determine the influence on tumour ERBB-RAS pathway activity and progression from early stage disease. Use Our data will determine the value of ERBB signalling as a predictive indicator of KRAS LuAd progression. Our detection methods could be rapidly applied in the clinic and moreover guide patient-specific cancer therapy with existing approved drugs.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS