Fig. 4

Conditions under which minimal residual tumor cells in molecular drug resistance can emerge. (1) Intrinsic resistance describes the cells’ inherent ability to resist the drug during initial therapy with preexisting stable genetic/genomic drug-resistant alteration(s). Shown are pretreatment lung adenocarcinoma cells harboring only the activating EGFR L858R mutation and cells that are double mutant for EGFR L858R and T790M. The T790M-mutants can survive initial treatments with an EGFR inhibitor (EGFRi) erlotinib or gefitinib, leading to incomplete response and eventual therapy failure and tumor progression stemmed from the expansion of the T790M clones. (2) Tumor cells adapt under therapeutic pressure to activate the early adaptive drug resistance program, engaging a cellular omics reprogramming scheme such as shift or modulation of prosurvival signaling, EMT-ness, cancer stemness and plasticity, glycolytic Warburg genes, among other undiscovered mechanisms. Drug-resistant molecular residual disease cells emerge as a result. As shown here in illustration, the STAT3/BCL-2/BCL-xL mitochondrial prosurvival signaling concurrent with hyperactivation of the TGFβ signaling pathway promote a drug-tolerant state that enables drug persistence during initial EGFR-TKI treatment. (3) The tumor microenvironment potentially contributes to the adaptive evolution of the tumor cells, resulting in minimal residual disease. As illustrated, stromal cells surrounding lung adenocarcinoma cells that secrete high levels of TGFβ have been known to stimulate the TGFβ axis in tumor cells via autocrine or paracrine signaling, granting them independence from EGFR signaling. TGFβ signals through IL-6, gp130, and JAK2 to stimulate STAT3 homodimerization. (4) Pharmacologic limitations, dose-limiting toxicities, or tumor intrinsic barriers can result in poor drug penetration into the tumor, resulting in pharmacokinetic therapy failure